Cyclic amide derivatives

ABSTRACT

The present invention provides novel cyclic amide derivatives having activity for protecting against the ultraviolet rays, activity for scavenging active oxygen species and activity for inhibiting the formation of lipid peroxides, which is represented by the following general formula (1): ##STR1## wherein R 2  is a hydroxyl group, a lower alkenyloxy group, a phenyl-lower alkenyloxy group, a cycloalkenyloxy group, a tetrahydropyranyloxy group, a pyridyloxy group, or a lower alkanoyloxy group which may have carboxyl group(s).

FIELD OF THE INDUSTRIAL UTILIZATION

The present invention relates to novel cyclic amide derivatives andsalts thereof.

BACKGROUND ART

The sunlight is indispensable environmental factor to the living body,while at the same time the sunlight is harmful to the living body. Theskin and eyes are contacted continuously with oxygen in the air,additionally these organs are unavoidably encountered in the environmentwhere active oxygen species and lipid peroxides are formed easily byphysical reactions caused by direct effect of the ultraviolet rays andradiations, and by chemical reactions in the presence of the sebum andother chemical substances. (Cf. Pharma. Medica., 1990, Vol. 8, No. 4,pp. 67-71). Harmful effects caused by the sunlight to the living bodyare mostly made on the basis of actions of ultraviolet rays. Among theultraviolet rays, ultraviolet ray-C has the highest energy level andshows strong germicidal activity, and is also known that it acceleratesthe cancerization. Ultraviolet ray-C is absorbed in the ozonosphere inthe stratosphere surrounding the earth, so that very little amount ofultraviolet ray-C only reaches the earth ground. Ultraviolet ray-Acauses pigmentation of the skin due to increase of melanin formation inthe skin. Ultraviolet ray-B causes sunburn, such as "feel hot" andvaricella, and it has been known that the skin cancerization may becaused by long hour-exposure to the ultraviolet ray-B. (Cf. Activeoxygen . Free radicals, 1993, Vol. 4, pp. 20-22).

In recent years, it has been well known as the fact that thecancerization tends to upward by increasing of irradiated amount ofultraviolet ray-B due to destruction of the ozonosphere. Thesedisturbances and injuries of the living body caused by ultraviolet raysare presumed on the basis of various active oxygen radicals which areformed by exposure to the ultraviolet rays.

Formation of the active oxygen species caused by exposure to theultraviolet rays is proposed as two types of mechanisms as follows. Thatis, one type of the mechanism is that the substrate (e.g., lipid) isoxidized and/or reduced by reacting with excited state of sensitizedmaterials which are excited by action of the ultraviolet rays or lights.Then, oxygen is added to the substrate, which is changed to radicalstate, to form peroxide (lipid peroxide). Further, oxygen anion radicalsare formed by transformation of electrons from the radical to oxygen.Another type of formation mechanism is that the sensitized materials inexcited state are first reacted with oxygen, so that energy or electrontransfer causes the formation of singlet oxygen or oxygen anion radical.Furthermore, hydrogen peroxide is formed from oxygen anion radical bydisproportionation, and hydroxy radicals are also formed by Fentonreaction (Cf. Active Oxygen . Free Radicals, 1993, Vol. 4, pp. 6-19).

Pharmaceutical chemicals which possess activities for scavenging theseoxygen radicals can be used as agents for prevention and treatment ofvarious injuries and diseases caused by the ultraviolet rays. Inaddition to the above, superoxide dismutases (SOD), which actdisproportionation against oxygen anion radicals, present in the livingbodies (Cf. Journal of Investigative Dermatology, 1984, Vol. 83, pp.166-168), and there are known some agents for preventing and treatingdermatological injuries which are caused by active oxygen speciespresent in the living bodies Cf. Hifuka Kiyou (Bulletin of Dermatology(Japan)), 1987, Vol. 82, No. 2, pp. 179-182!. Glutathione is known thatit possesses activity for scavenging alkoxy radicals, so that it is usedas treating agent of cataract. Vitamin E possesses skin protectionactivity (Cf. Fragrance Journal, 1991, No. 8, pp. 28-33). Vitamin Cpossesses anti-oxidation activity, and is known that it is effective toprevention of pigmentation (Cf. Fragrance Journal and Biophysics, 1992,Vol. 296, No. 2, pp. 575-582; Journal of Dermatology, 1990, Vol. 17, pp.595-598). However, it should be noted the fact that, because SOD andglutathione are endgenous substances, they have some problems instabilities thereof and raw materials obtained therefor are not easilyavailable. Also, these vitamins have problems because their stabilitiesand the effects in vivo are not good enough.

In view of these circumstances, the present inventors have madeextensive research works and as the result that the present inventionhave successfully completed based on the finding of the facts that thecyclic amide derivatives of the present invention possess effectivescavenging activities against active oxygen species, and said cyclicamide derivatives clearly show the activities for decreasing andremoving lipid superoxides, which are formed increasingly in the livingbodies, by irradiation of ultraviolet rays.

DISCLOSURE OF THE INVENTION

The cyclic amide derivatives of the present invention are novelcompounds which have not been known in any literature, and arerepresented by the general formula (1) as follows: ##STR2## wherein R²is a hydroxyl group, a lower alkenyloxy group, a phenyl-lower alkenyloxygroup, a cycloalkenyloxy group, a tetrahydropyranyloxy group, apyridyloxy group, or a lower alkanoyloxy group which may have carboxygroup(s);

R³ is a lower alkenyl group;

Z is an oxygen atom, a sulfur atom, a group of --CH₂ --, or a group of--CH═CH--;

n is an integer of 1 to 3;

m is 0 or 1; provided that when Z is a group of --CH═CH--, then m is 0;

R¹ is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl-loweralkenyl group, a cycloalkyl-lower alkyl group, a phenyl group which mayhave, in the phenyl ring, substituent(s) selected from the groupconsisting of a lower alkoxy group and a halogen atom, a hydroxylgroup-substituted alkyl group, a halogen-substituted lower alkyl group,a cycloalkenyl group; a lower alkynyl group, a phenyl-lower alkyl groupwhich may have, on the phenyl ring, 1 to 3 substituents selected fromthe group consisting of a lower alkenyloxy group, a lower alkoxy group,a lower alkenyl group, a hydroxyl group, a lower alkyl group, a carboxylgroup, a lower alkoxycarbonyl group and a group of the formula: ##STR3##a naphthyl-substituted lower alkyl group, a phthalimido-substitutedlower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group,a group of the formula: ##STR4## (wherein A is a lower alkylene group;R⁴ and R⁵ are the same or different, and are each a hydrogen atom, acarbamoyl group, a lower alkanoyl group which may have halogen atom(s),a phenylsulfonyl group which may have, in the phenyl ring, lower alkylgroup(s) as substituent(s), a lower alkoxy-lower alkyl group, a loweralkyl group, a hydroxyl group-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, or a carboxy-substitutedlower alkyl group; further R⁴ and R⁵ may form 5- or 6-membered saturatedor unsaturated hetero-cyclic group by combining to each other, togetherwith the adjacent nitrogen atom being bonded thereto, further with orwithout other nitrogen atom or oxygen atom; said heterocyclic group mayhave, as substituent(s) selected from the group consisting of acarbamoyl group, a carboxyl group, a cycloalkyl group and a phenyl groupwhich may have halogen atom(s) as substituent in the phenyl ring);

a lower alkanoyloxy-lower alkyl group, a cyano group-substituted loweralkyl group, a group of the formula: ##STR5## (wherein, A is a loweralkylene group; R⁹ and R¹⁰ are the same or different, and are each ahydrogen atom or a lower alkyl group), a carboxy-substituted lower alkylgroup, a lower alkoxycarbonyl-substituted lower alkyl group or acarbamoyl-substituted lower alkyl group.

An object of the present invention is to provide cyclic amidederivatives and salt thereof, having activity for protecting injuriesfrom ultraviolet rays, activity for scavenging active oxygen radicals,activity for inhibiting formation of lipid peroxides, and they areuseful as active ingredients to be contained in pharmaceuticalcomposition, medicines of external use, eye lotion, medicated cosmeticsand common cosmetics for preventing and treating various diseases causedby exposure to ultraviolet rays, contact with active oxygen species andlipid peroxides.

As to the active oxygen species, there can be exemplified hydroxyradical, alkoxy radical, hydroperoxy radical, peroxy radical,superoxide, hydrogen peroxide, hydroperoxide, singlet oxygen, ozone andothers.

The cyclic amide derivatives of the present invention clearly inhibitthe formation of lipid peroxides in the skin caused by exposure toultraviolet rays. Furthermore, the cyclic amide derivatives of thepresent invention trap a radical from diphenylpicrylhydrazyl, which isunderstood as a typical model of lipid peroxides. For these reasons, thecyclic amide derivatives of the present invention are useful as agentsfor preventing and treating various dermatological injuries and variousdiseases which are caused by ultraviolet rays, active oxygen species,radicals and lipid peroxides, as well as agent for preventing aging ofthe skin Cf. Hifubyo Shinryo (Treatment of Dermatitis (Japan)), 1991,Vol. 13, No. 3, pp. 201-205; Fragrance Journal, 1993, No. 11, pp.35-42!. For example, the cyclic amide derivatives of the presentinvention are useful as agents for preventing and treating solardermatitis, precancerous lesions of the skin (containing solarkeratosis), malignant tumors of the skin, hyperpigmentation such asmelasma, ephelides, senile pigment freckle, pigmentatio petaloidesactinica; chronic actinic dermatoses such as sailor's skin, farmer'sskin, cutis rhomboidalis nuchae, cheilitis actinica, senile atrophy,seborrheic keratosis; photocontact dermatitis, berlick dermatitis, skinvascular inflammation, erythema multiforme, Bechcet's disease, varicelladermatitis, cement dermatitis, neurodermatitis, eczema, pruritus aroundanal or genital region, dermatitis of human beings, skin diseases ofmammals other than human beings (e.g., pet animals such as dogs andcats, and domestic cattles such as cows and horses), photosensitivedermatoses such as photosensitizing drug eruption, polymorphous lighteruption, hydroa vacciniforme, solar urtiaria and porphyria, and burninjury (Burns, 1989, Vol. 15, No. 5, pp. 291-294 and Ibid., 1992, Vol.18, No. 2, pp. 127-131); keloid, comedo, atopic dermatitis, contactdermatitis, diaper dermatitis, seborrheic dermatitis, autosensitizationdermatitis, stasis dermatitis, urticaria, prurigo, pruritus cutaneous,keratosis such as psoriasis, lichen planus, follicular keratosis,pityriasis, and used as cosmetics and medicines for external use(including medicated cosmetics) for protection of sunburn, prevention ofmelasma and ephelides caused by sunburn, prevention of wrinkles, agingof the skin and photoaging; and also useful as active ingredient forquasi-drugs (Cf. Active Oxygen . Free Radicals, 1992, Vol. 3, pp.306-311). In addition to the activity for scavenging active oxygenspecies, the cyclic amide derivatives of the present invention areuseful as agent for preventing cataract because they possess excellentproperty of transference to the aqueous humor (Cf. Active Oxygen . FreeRadicals, 1993, Vol. 4, pp. 20-26).

The cyclic amide derivatives of the present invention are useful asagents for preventing and treating various disturbances and diseasesother than those mentioned above, caused by active oxygen radicals. Asto the agents for preventing and treating various disturbances anddiseases, for example, agent of antiarteriosclerosis, agent forpreventing cancerization, carcinostatic agent, antiiflammatory agent,analgesic, agent for treating autoimmune diseases, agent for inhibitingaggregation of platelets, hypotensive agent, antihyperlipidemia agentand agent for preventing and treating retinopathy of prematurity.Further, the cyclic amide derivatives of the present invention areuseful as agents for treating diseases of various organs, for examplethe heart, the kidney, the digestive tract, the brain, ischematicdiseases in the nervous system, ischematic heart diseases such asmyocardial infarction and arrhythmia; agents for improving disturbancesof hepatic and renal functions caused by transplantation andmicrocirculation disfunction; agents for treating digestive tract ulcerssuch as gastric ulcer; agents for treating cerebral hemorrhage, cerebralinfarction and transient ischematic cerebral attack; agents for treatingdisturbances such as decreasing the number of leukocytes, alopecia,reddening of the skin, vomiting, anorexia and the like which are causedby exposure to radiations such as X ray, α ray, β ray, γ ray, neutronbeam, accelerated electron beam and the like; agents for treatingdiabetes mellitus, ophthalmological diseases such as siderosis ofeyeball, retinitus and the like; pigmentation, sepsis, pulmonary edema,adult respiratory distress syndrome, common arthritis, malignantrheumatic arthritis, ulcerative colitis, Crohn's disease, Parkinson'sdisease and Raynau's disease, as well as burn injury, external injury,fatigue and the like. Furthermore, the cyclic amide derivatives of thepresent invention are useful not only as use of the above-mentionedpharmaceutical applications, but also effective as use of otherindustrial fields such as antioxidation agents for oils and fats beingcontained in processed food products and the like.

In the present specification, concrete examples of the substituents areshown as follows.

As to the lower alkenyloxy group, a straight chain- or branchedchain-alkenyloxy group having 2 to 6 carbon atoms, such as vinyloxy,allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxyand 2-hexenyloxy groups can be exemplified.

As to the phenyl-lower alkenyloxy group, a phenyl-alkenyloxy group inwhich the alkenyl moiety is a straight chain- or branched chain-alkenylgroup having 2 to 6 carbon atoms, such as styryloxy, cinnamyloxy,2-phenyl-2-butenyloxy, 3-phenyl-3-butenyloxy, 1-methyl-2-phenylallyloxy,5-phenyl-2-pentenyloxy and 6-phenyl-2-hexenyloxy groups can beexemplified.

As to the cycloalkenyloxy group, a cycloalkenyloxy group having 3 to 8carbon atoms, such as cyclopropenyloxy, cyclobutenyloxy,cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy and cyclooctenyloxygroups can be exemplified.

As to the lower alkanoyloxy group which may have carboxyl group(s) asthe substituent(s), a straight chain- or branched chain-alkanoyloxygroup having 1 to 6 carbon atoms which may have 1 to 3 carboxyl groupsas the substituents, such as formyloxy, acetyloxy, propionyloxy,butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy,hexanoyloxy, 2-carboxyacetyloxy, 2,2-dicarboxyacetyloxy,3,3,3-tricarboxypropionyloxy, 3-carboxypropionyloxy,4,4,4-tricarboxybutyryloxy, 4-carboxybutyryloxy, 5-carboxypentanoyloxy,3-carboxy-2-methylpropionyloxy, 6-carboxyhexanoyloxy and5,6-dicarboxyhexanoyloxy groups can be exemplified.

As to the alkyl group, a straight chain- or branched chain-lower alkylgroup having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl and hexyl groups can beexemplified, and a straight chain- or branched chain-alkyl group having7 to 12 carbon atoms, such as heptyl, octyl, nonyl, decyl, undecyl,dodecyl, 3-ethylpentyl, 2,3,5-trimethylhexyl, and 5-methyl-4-propyloctylgroups can be exemplified.

As to the alkenyl group, a straight chain- or branched chain-alkenylgroup having 2 to 11 carbon atoms and having 1 to 3 double bondingtherein, such as vinyl, allyl, 3-methylbutenyl, 2-butenyl, 3-butenyl,1-methylallyl, 2-pentenyl, 2-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl,1-decenyl, 1-undecenyl, 2-heptenyl, 3-heptenyl, 2-methyl-4-heptenyl,2-methyl-5-heptenyl, 4-methyl-2-heptenyl, 3-methyl-1-heptenyl,2,4-butadienyl, 1,3-pentadienyl, 2,4-hexadienyl, 1,3,5-hexatrienyl,1,3-heptadienyl, 1,4-heptadienyl, 1,5-heptadienyl, 1,6-heptadienyl,2,4-heptadienyl, 2-methyl-2,4-heptadienyl, 2,6-dimethyl-2,4-heptadienyl,2,5-dimethyl-1,3-heptadienyl, 2,4,6-trimethyl-2,4-heptadienyl,2-octenyl, 3-octenyl, 4-octenyl, 2-methyl-5-octenyl, 2-methyl-6-octenyl,2-methyl-7-octenyl, 1,3-octadienyl, 1,4-octadienyl, 1,5-octadienyl,1,6-octadienyl, 1,7-octadienyl, 2,4-octadienyl, 3,7-octadienyl,4,8-dimethyl-3,7-octadienyl, 2,4,6-trimethyl-3,7-octadienyl,3,4-dimethyl-2,5-octadienyl, 3,7-dimethyl-2,6-octadienyl,4,8-dimethyl-2,6-octadienyl, 2-nonenyl, 3-nonenyl, 4-nonenyl,2-methyl-5-nonenyl, 2-methyl-6-nonenyl, 2-methyl-7-nonenyl,2-methyl-8-nonenyl, 1,3-nonadienyl, 1,4-nonadienyl, 1,5-nonadienyl,1,6-nonadienyl, 1,7-nonadienyl, 1,8-nonadienyl, 2,4-nonadienyl,3,7-nonadienyl, 4,8-dimethyl-3,7-nonadienyl,2,4,6-trimethyl-3,7-nonadienyl, 3,4-dimethyl-2,5-nonadienyl,4,8-dimethyl-2,6-nonadienyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl,2-methyl-6-decenyl, 3-methyl-7-decenyl, 4-methyl-8-decenyl,5-methyl-9-decenyl, 1,3-decadienyl, 1,4-decadienyl, 1,5-decadienyl,1,6-decadienyl, 1,7-decadienyl, 1,8-decadienyl, 1,9-decadienyl,2-methyl-2,4-decadienyl, 3-methyl-2,5-decadienyl,4,8-dimethyl-2,6-decadienyl, 2,4,6-trimethyl-3,7-decadienyl,2,9-dimethyl-3,7-decadienyl, 2-undecenyl, 3-undecenyl, 4-undecenyl,5-undecenyl, 2-methyl-6-undecenyl, 3-methyl-7-undecenyl,4-methyl-8-undecenyl, 5-methyl-9-undecenyl, 2-methyl-10-undecenyl,1,3-undecadienyl, 1,4-undecadienyl, 1,5-undecadienyl, 1,6-undecadienyl,1,7-undecadienyl, 1,8-undecadienyl, 1,9-undecadienyl, 1,10-undecadienyl,2-methyl-2,4-undecadienyl, 3-methyl-2,5-undecadienyl,4,8-dimethyl-2,6-undecadienyl, 2,4,6-trimethyl-3,8-undecadienyl,2,9-dimethyl-3,8-uecadienyl, 1,3,5-heptatrienyl, 2,4,6-octatrienyl,1,3,6-nonatrienyl and 1,5,7-undecatrienyl groups can be exemplified.

As to the phenyl-lower alkenyl group, a phenyl-alkenyl group in whichthe alkenyl moiety is a straight chain- or branched chain-alkenyl grouphaving 2 to 6 carbon atoms, such as styryl, cinnamyl,2-phenyl-2-butenyl, 3-phenyl-3-butenyl, 1-methyl-2-phenylallyl,5-phenyl-2-pentenyl and 6-phenyl-2-hexenyl group can be exemplified.

As to the cycloalkyl-lower alkyl group, a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms to which a cycloalkyl grouphaving 3 to 8 carbon atoms is bonded, such as cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentyl-propyl,cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl,4-cyclohexylbutyl, 3-cyclobutylpropyl, 1,1-dimethyl-2-cyclohexylethyl,1-methyl-2-cyclopentylethyl, 2-cyclooctylethyl, 4-cyclohexylbutyl,2-cyclopentylethyl, 2-cyclohexyl-propyl, 2-cycloheptylethyl,5-cyclohexylpentyl and 6-cyclohexylhexyl groups can be exemplified.

As to the phenyl group which may have as substituents selected from thegroup consisting of a lower alkoxy group(s) and a halogen atom(s) in thephenyl ring, a phenyl group which may have 1 to 3 substituents selectedfrom the group consisting of a straight chain- or branched chain-alkoxygroup having 1 to 6 carbon atoms and a halogen atom in the phenyl ring,such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl,4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl,2,5-dimethoxyphenyl, 3,4,5-trimetoxyphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl,3,4,5-trichlorophenyl and 2-ethoxy-4-chlorophenyl groups can beexemplified.

As to the hydroxyl group-substituted alkyl group, a straight chain- orbranched chain-alkyl group having 1 to 11 carbon atoms to which 1 to 3hydroxyl groups are substituted, such as hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypentyl, 2-hydroxypentyl,3-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl, 2-hydroxyhexyl,3-hydroxyhexyl, 4-hydroxyhexyl, 1-methyl-2-hydroxyethyl,1,1-dimethyl-2-hydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl,1,3-dihydroxypropyl, 2,3-dihydroxypropyl, 1,2,3-trihydroxypropyl,1,4-dihydroxybutyl, 2,4-dihydroxybutyl, 3,4-hydroxybutyl,1,2-dihydroxybutyl, 2,3-dihydroxybutyl, 1,3-dihydroxybutyl,2,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, 2,3,4-trihydroxybutyl,2,3-dihydroxypentyl, 3,4-dihydroxypentyl, 3,5-dihydroxypentyl,3,4,5-trihydroxypentyl, 2,4,5-trihydroxypentyl, 2,3-dihydroxyhexyl,3,4-dihydroxyhexyl, 3,5-dihydroxyhexyl, 3,4,5-trihydroxyhexyl,2,4,5-trihydroxyhexyl, 7-hydroxyheptyl, 8-hydroxyoctyl, 9-hydroxynonyl,10-hydroxydecanyl and 11-hydroxyundecanyl groups can be exemplified.

As to the halogen-substituted alkyl group, a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms to which 1 to 3 halogenatoms are substituted, such as chloromethyl, 2-chloroethyl,3-chloropropyl, 2-chloropropyl, 2-chloroisopropyl, 2-chlorobutyl,3-chlorobutyl, 4-chlorobutyl, 5-chloropentyl, 2-chloropentyl,3-chloropentyl, 4-chloropentyl, 6-chlorohexyl, 2-chlorohexyl,3-chlorohexyl, 4-chlorohexyl, 1-methyl-2-chloroethyl,1,1-dimethyl-2-chloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl,1,3-dichloropropyl, 2,3-dichloropropyl, 1,2,3-trichloropropyl,1,4-dichlorobutyl, 2,4-dichlorobutyl, 3,4-dichlorobutyl,1,2-dichlorobutyl, 2,3-dichlorobutyl, 1,3-dichlorobutyl,2,2-dichlorobutyl, 1,2,3-trichlorobutyl, 2,3,4-trichlorobutyl,2,3-dichloropentyl, 3,4-dichloropentyl, 3,5-dichloropentyl,3,4,5-trichloropentyl, 2,4,5-trichloropentyl, 2,3-dichlorohexyl,3,4-dichlorohexyl, 3,5-dichlorohexyl, 3,4,5-trichlorohexyl,2,4,5-trichlorohexyl, bromomethyl, 2-bromoethyl, 3-boromopropyl,2-bromopropyl, 2-bromoisopropyl, 2-bromobutyl, 3-bromobutyl,4-bromobutyl, 5-bromopentyl, 2-bromopentyl, 3-bromopentyl,4-bromopentyl, 6-bromohexyl, 2-bromohexyl, 3-bromohexyl, 4-bromohexyl,1-methyl-2-bromoethyl, 1,1-dimethyl-2-bromoethyl, 1,2-dibromoethyl,2,2-dibromoethyl, 1,3-dibromopropyl 2,3-dibromopropyl,1,2,3-tribromopropyl, 1,4-dibromobutyl, 2,4-dibromobutyl,3,4-dibromobutyl, 1,2-dibromobutyl, 2,3-dibromobutyl, 1,3-dibromobutyl,2,2-dibromobutyl, 1,2,3-tribromobutyl, 2,3,4-tribromobutyl,2,3-dibromopentyl, 3,4-dibromopentyl, 3,5-dibromopentyl,3,4,5-tribromopentyl, 2,4,5-tribromopentyl, 2,3-dibromohexyl,3,4-dibromohexyl, 3,5-dibromohexyl, 3,4,5-tribromohexyl,2,4,5-tribromohexyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl,2-fluoropropyl, 2-fluoroisopropyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl, 5-fluoropentyl, 2-fluoropentyl, 3-fluoropentyl,4-fluoropentyl, 6-fluorohexyl, 2-fluorohexyl, 3-fluorohexyl,4-fluorohexyl, 1-methyl-2-fluoroethyl, 1,1-dimethyl-2-fluoroethyl,1,2-difluoroethyl, 2,2-difluoroethyl, 1,3-difluoropropyl,2,3-difluoropropyl, 1,2,3-trifluoropropyl, 1,4-difluorobutyl,2,4-difluorobutyl, 3,4-difluorobutyl, 1,2-difluorobutyl,2,3-difluorobutyl, 1,3-difluorobutyl, 2,2-difluorobutyl,1,2,3-trifluorobutyl, 2,3,4-trifluorobutyl, 2,3-difluoropentyl,3,4-difluoropentyl, 3,5-difluoropentyl, 3,4,5-trifluoropentyl,2,4,5-trifluoropentyl, 2,3-difluorohexyl, 3,4-difluorohexyl,3,5-difluorohexyl, 3,4,5-trifluorohexyl, 2,4,5-trifluorohexyl,iodomethyl, 2-iodoethyl, 3-iodopropyl, 2-iodopropyl, 2-iodoisopropyl,2-iodobutyl, 3-iodobutyl, 4-iodobutyl, 5-iodopentyl, 2-iodopentyl,3-iodopentyl, 4-iodopentyl, 6-iodohexyl, 2-iodohexyl, 3-iodohexyl,4-iodohexyl, 6-iodohexyl, 2-iodohexyl, 3-iodohexyl, 4-iodohexyl,1-methyl-2-iodoethyl, 1,1-dimethyl-2-iodoethyl, 1,2-diiodoethyl,2,2-diiodoethyl, 1,3-diiodopropyl, 2,3-diiodopropyl,1,2,3-triiodopropyl, 1,4-diiodobutyl, 2,4-diiodobutyl, 3,4-diiodobutyl,1,2-diiodobutyl, 2,3-diiodobutyl, 1,3-diiodobutyl, 2,2-diiodobutyl,1,2,3-triiodobutyl, 2,3,4-triiodobutyl, 2,3-diiodopentyl,3,4-diiodopentyl, 3,5-diiodopentyl, 3,4,5-triiodopentyl,2,4,5-triiodopentyl, 2,3-diiodohexyl, 3,4-diiodohexyl, 3,5-diiodohexyl,3,4,5-triiodohexyl, 2,4,5-triiodohexyl, 1-chloro-2-bromoethyl, and2-chloro-4-fluorobutyl groups can be exemplified.

As to the cycloalkenyl group, a cycloalkenyl group having 3 to 8 carbonatoms, such as cyclopropenyl, cyclobutynyl, cyclopentynyl, cyclohexenyl,cycloheptenyl and cyclooctenyl groups can be exemplified.

As to the lower alkynyl group, a straight chain- or branchedchain-alkynyl group having 2 to 6 carbon atoms, such as ethynyl,2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl and2-hexynyl groups can be exemplified.

As to the lower alkoxy group, a straight chain- or branched chain-alkoxygroup having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups can beexemplified.

As to the phenyl-lower alkyl group which may have 1 to 3 substituentsselected from the group consisting of a lower alkenyloxy group, a loweralkoxy group, a lower alkenyl group, a hydroxyl group, a lower alkylgroup, a carboxyl group, a lower alkoxycarbonyl group and a group of theformula: ##STR6## in the phenyl ring; a phenylalkyl group in which thealkyl moiety is a straight chain- or branched chain-alkyl group having 1to 6 carbon atoms, said phenyl-alkyl group may have 1 to 3 substituentsselected from the group consisting of a straight chain- or branchedchain-alkenyloxy group having 2 to 6 carbon atoms, a straight chain- orbranched chain-alkoxy group having 1 to 6 carbon atoms, a straightchain- or branched chain-alkenyl group having 1 to 6 carbon atoms, ahydroxyl group, a straight chian- or branched chain-alkyl group having 1to 6 carbon atoms, a carboxyl group, a carbonyl group having a straightchain- or branched chain-alkoxy group having 1 to 6 carbon atoms and agroup of the formula: ##STR7## in the phenyl ring, such as benzyl,2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, 5-phenylpentyl,6-phenylhexyl, 2-vinyloxybenzyl, 3-vinyloxybenzyl, 3-allyloxybenzyl,4-allyloxybenzyl, 3,4-divinyloxybenzyl, 3,4,5-triallyloxybenzyl, 2-2-(2-butenyloxy)phenyl!ethyl, 3- 3-(1-methylallyloxy)-phenyl!propyl, 4-4-(2-pentenyloxy)phenyl!butyl, 5- 2-(2-hexenyloxy)phenyl!pentyl, 5-3-(3-butenyloxy)-phenyl!ethyl, 2- 3,4-di-(2-butenyloxy)phenyl!ethyl,2-(3,4-diallyloxyphenyl)ethyl, 1-(3,4-vinyloxypheyl)-ethyl,2-(3,4,5-triallyloxyphenyl)ethyl, 3-(3,4-diallyloxyphenyl)propyl,4-(3,4-diallyloxyphenyl)butyl, 6-(3,4-diallyloxyphenyl)hexyl,1,1-dimethyl-2-(3,4-diallyloxyphenyl)ethyl,2-(2,5-diallyloxyphenyl)ethyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 3-ethoxy-4-methoxybenzyl,3,4,5-trimethoxybenzyl, 2-(2-ethoxyphenyl)ethyl,2-(3,4-dipropoxyphenyl)ethyl, 3-(3-propoxyphenyl)propyl,4-(4-butoxyphenyl)butyl, 5-(2-pentyloxyphenyl)pentyl,6-(3-hexyloxyphenyl)hexyl, 2-(4-isopropoxyphenyl)ethyl,2-(3,4-diisopropoxyphenyl)ethyl, 2-(3,4-dibutoxyphenyl)ethyl,1-(3,4-diethoxyphenyl)ethyl, 2-(3,4,5-trimethoxyphenyl)ethyl,3-(3,4-dimethoxyphenyl)propyl, 4-(3,4-dimethoxyphenyl)butyl,6-(3,4-dimethoxyphenyl)-hexyl,1,1-dimethyl-2-(3,4-dimethoxyphenyl)ethyl, 2-(2,5-dimethoxyphenyl)ethyl,2-vinylbenzyl, 3-vinylbenzyl, 4-allylbenzyl, 3,4-divinylbenzyl,3,4,5-triallylbenzyl, 2-(2-vinylphenyl)ethyl, 2-3-(1-methylallyl)phenyl!ethyl, 3- 4-(2-butenyl)phenyl!-propyl 4-3-(3-butenyl)phenyl!butyl, 5- 2-(2-pentenyl)phenyl!pentyl, 2-3,4-di-(2-butenyl)-phenyl!ethyl, 2-(3,4-diallylphenyl)ethyl, 6-4-(2-hexenyl)phenyl!hexyl, 2-(3,4,5-triallylphenyl)ethyl,3-(3,4-diallylphenyl)propyl, 4-(3,4-diallylphenyl)-butyl,6-(3,4-diallylphenyl)hexyl, 1,1-dimethyl-2-(3,4-diallylphenyl)ethyl,2-(2,5-diallylphenyl)ethyl, 2-hydroxybenzyl, 3-hydroxybenzyl,4-hydroxybenzyl, 3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl,2-(2-hydroxyphenyl)ethyl, 2-(3-hydroxyphenyl)ethyl,2-(4-hydroxyphenyl)ethyl, 2-(3,4-dihydroxyphenyl)ethyl,2-(3,4-diethoxyphenyl)ethyl, 2-(3,4-diisopropoxyphenyl)ethyl,2-(3,4-dibutoxyphenyl)ethyl, 1-(3,4-dihydroxyphenyl)ethyl,2-(3,4,5-trihydroxyphenyl)ethyl, 3-(3,4-dihydroxyphenyl)propyl,4-(3,4-dihydroxyphenyl)butyl, 6-(3,4-dihydroxyphenyl)hexyl,1,1-dimethyl-2-(3,4-dihydroxyphenyl)ethyl, 2-(2,5-dihydroxyphenyl)ethyl,2-methylbenzyl, 3-methylbenzyl, 4-ethylbenzyl, 4-methylbenzyl,2-ethylbenzyl, 3-ethylbenzyl, 3,4-dimethylbenzyl, 3,4,5-trimethylbenzyl,2-(2-methylphenyl)ethyl, 2- 3-(2-ethyl)phenyl!ethyl,2-(3,4-dimethylphenyl)ethyl, 2- 3,4-di-(4-butyl)-phenyl!ethyl,2-(3,5-dimethylphenyl)ethyl, 1- 3,4-di-(2-ethyl)phenyl!ethyl, 2-3,4,5-tri-(2-ethyl)phenyl!-ethyl, 3-(3,4-dimethylphenyl)propyl,4-(3,4-dimethylphenyl)butyl, 6-(3,4-dimethylphenyl)hexyl,1,1-dimethyl-2-(3,4-dimethylphenyl)ethyl, 2-(2,5-dimethylphenyl)ethyl,3-(2-pentylphenyl)propyl, 4-(3-butylphenyl)butyl,5-(4-hexylphenyl)pentyl, 6-(2-methylphenyl)hexyl, 2-carboxybenzyl,3-carboxybenzyl, 4-carboxybenzyl, 3,4-dicarboxybenzyl,3,4,5-tricarboxybenzyl, 2-(2-carboxyphenyl)ethyl,2-(3-carboxyphenyl)ethyl, 2-(4-carboxyphenyl)ethyl,2-(3,4-dicarboxyphenyl)ethyl, 1-(3,4-dicarboxyphenyl)-ethyl,2-(3,4,5-tricarboxyphenyl)ethyl, 3-(3,4-dicarboxyphenyl)propyl,4-(3,4-dicarboxyphenyl)butyl, 6-(3,4-dicarboxyphenyl)hexyl,1,1-dimethyl-2-(3,4-dicarboxyphenyl)ethyl, 2-(2,5-dicarboxyphenyl)ethyl,2-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl,4-methoxycarbonylbenzyl, 3,4-dimethoxycarbonylbenzyl,3,4,5-trimethoxycarbonylbenzyl, 2-(2-ethoxycarbonylphenyl)ethyl,3-(3-propoxycarbonylphenyl)propyl, 4-(4-butoxycarbonylphenyl)butyl,5-(2-pentyloxycarbonylphenyl)pentyl, 6-(3-hexyloxycarbonylphenyl)-hexyl,2-(3,4-diisopropoxycarbonylphenyl)ethyl,2-(3,4-dibutoxycarbonylphenyl)ethyl,1-(3,4-diethoxycarbonylphenyl)ethyl,2-(3,4,5-trimethoxycarbonylphenyl)ethyl,3-(3,4-dimethoxycarbonylphenyl)propyl,4-(3,4-dimethoxycarbonylphenyl)butyl,6-(3,4-dimethoxycarbonylphenyl)hexyl,1,1-dimethyl-2-(3,4-dimethoxycarbonylphenyl)ethyl,2-(2,5-dimethoxycarbonylphenyl)-ethyl,2-(3,4-diethoxycarbonylphenyl)ethyl,2-(3,4-diisopropoxycarbonylphenyl)ethyl,2-(3,4-dibutoxycarbonylphenyl)ethyl,2-(4-isopropoxycarbonylphenyl)-ethyl,3-ethoxycarbonyl-4-methoxycarbonylbenzyl, 3-allyl-4-hydroxybenzyl,4-hydroxy-3-allyl-2-methylphenyl, 3,5-diallyl-4-hydroxybenzyl and(5,7-diallyl-4-hydroxy-3,4-dihydrocarbostyril-1-yl)methyl!benzyl groupscan be exemplified.

As to the naphthyl-substituted lower alkyl group, a naphthyl-substitutedalkyl group in which the alkyl moiety is a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms, such as naphthylmethyl,2-naphthylethyl, 3-naphthylpropyl, 1-methyl-2-naphthylethyl,4-naphthylbutyl, 1,1-dimethyl-2-naphthylethyl, 5-naphthylpentyl,6-naphthylhexyl and 2-methyl-3-naphthylpropyl groups can be exemplified.

As to the phthalimido-substituted lower alkyl group, aphthalimido-substituted alkyl group in which the alkyl moiety is astraight chain- or branched chain-alkyl group having 1 to 6 carbonatoms, such as phthalimidomethyl, 2-phthalimidoethyl,3-phthalimidopropyl, 1-methyl-2-phthalimidoethyl, 4-phthalimidobutyl,1,1-dimethyl-2-phthalimidoethyl, 5-phthalimidopentyl, 6-phthalimidohexyland 2-methyl-3-phthalimidopropyl groups can be exemplified.

As to the lower alkoxycarbonyl-substituted lower alkyl group, analkoxycarbonylalkyl group in which the alkoxycarbonyl moiety is astraight chain- or branched chain-alkoxycarbonyl group having 1 to 6carbon atoms, and the alkyl moiety is a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms, such asmethoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl,4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl,1-methyl-2-methoxycarbonylethyl, 2-methoxycarbonylpropyl,1,1-dimethyl-2-methoxycarbonylethyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl,5-ethoxycarbonylpentyl, 6-ethoxycarbonylhexyl,1-methyl-2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl,1,1-dimethyl-2-ethoxycarbonylethyl, propoxycarbonylmethyl,2-propoxycarbonylethyl, 3-propoxycarbonylpropyl, 4-propoxycarbonylbutyl,5-propoxycarbonylhexyl, 2-propoxycarbonylpropyl,2-isopropoxycarbonylethyl, 2-butoxycarbonylethyl,3-butoxycarbonylpropyl, 4-butoxycarbonylbutyl, 6-butoxycarbonylpropyl,2-tertbutoxycarbonylethyl, 2-pentyloxycarbonylethyl,5-pentyloxycarbonylpentyl, 2-hexyloxycarbonylethyl and6-hexyloxycarbonylhexyl can be exemplified.

As to the lower alkylene group, a straight chain- or branchedchain-alkylene group having 1 to 6 carbon atoms, such as methylene,ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene and hexamethylene group can be exemplified.

As to the phenylsulfonyl group which may have lower alkyl group(s) asthe substituent(s) in the phenyl ring, a phenylsulfonyl group which mayhave 1 to 3 straight chain- or branched chain-alkyl groups having 1 to 6carbon atoms as the substituents in the phenyl ring, such asphenylsulfonyl, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl,4-methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenylsulfonyl,4-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl,4-butyl-phenylsulfonyl, 4-pentylphenylsulfonyl, 4-hexylphenylsulfonyl,3,4-dimethylphenylsulfonyl, 2,5-dimethylphenylsulfonyl and3,4,5-trimethylphenylsulfonyl groups can be exemplified.

As to the lower alkoxy-lower alkyl group, a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms to which a straight chain-or branched chain-alkoxy group having 1 to 6 carbon atoms issubstituted, such as methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl,1-methyl-2-methoxyethyl, 2-methoxypropyl, 1,1-dimethyl-2-methoxyethyl,ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl,5-ethoxypentyl, 6-ethoxyhexyl, 1-methyl-2-ethoxyethyl, 2-ethoxypropyl,1,1-dimethyl-2-ethoxyethyl, propoxymethyl, 2-propoxyethyl,3-propoxypropyl, 4-propoxybutyl, 5-propoxyhexyl, 2-propoxypropyl,2-isopropoxyethyl, 2-butoxyethyl, 3-butoxypropyl, 4-butoxybutyl,6-butoxyhexyl, 2-tert-butoxyethyl, 2-pentyloxyethyl, 5-pentyloxypentyl,2-hexyloxyethyl and 6-hexyloxyhexyl groups can be exemplified.

As to the phenyl group which may have halogen atom(s) as thesubstitutent(s) in the phenyl ring, a phenyl group which may have 1 to 3halogen atoms as the substituents in the phenyl ring, such as phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,3,5-dibromophenyl and 3,4,5-trichlorophenyl groups can be exemplified.

As to the 5- or 6-membered saturated or unsaturated heterocyclic groupby combining R⁴ and R⁵ together with the adjacent nitrogen atom beingbonded thereto together with or without other nitrogen atom or oxygenatom, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolyl,imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrazolyl, 2-pyrrolinyl,2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,1,2-dihydropyridyl, 1,2,3,4-tetrahydropyridyl and 1,2,3,4-tetrazolylgroups can be exemplified.

As to the heterocyclic group having substituent(s) selected from thegroup consisting of carbamoyl group, carboxyl group, cycloalkyl groupand a phenyl group which may have halogen atom(s) in the phenyl ring, aheterocyclic group having 1 to 3 substituents selected from the groupconsisting of a carbamoyl group, a carboxyl group, a cycloalkyl groupand a phenyl group which may have 1 to 3 halogen atoms in the phenylring, such as 2-carbamoylpyrrolidinyl, 3-carbamoylpyrrolidinyl,4-carbamoylpiperidinyl, 3-carbamoylpiperidinyl, 2-carbamoylpiperidinyl,4-carbamoylpiperazinyl, 3-carbamoylpiperazinyl, 2-carbamoylpiperazinyl,3-carbamoylmorpholino, 2-carbamoylmorpholino, 2-carbamoylpyrrolyl,3-carbamoylpyrrolyl, 2-carbamoylimidazolyl, 4-carbamoylimidazolyl,5-carbamoylimidazolyl, 3-carbamoyl-1,2,4-triazolyl,5-carbamoyl-1,2,4-triazolyl, 2-carbamoyl-1,2,4-triazolyl,5-carbamoylpyrazolyl, 3-carbamoylpyrazolyl, 2-carbamoyl-2-pyrrolinyl,3-carbamoyl-2-pyrrolinyl, 4-carbamoyl-2-pyrrolinyl,5-carbamoyl-2-pyrrolinyl, 2-carbamoyl-2-imidazolinyl,5-carbamoyl-1,2,3,4-tetrazolyl, 4-carbamoyl-2-imidazolinyl,5-carbamoyl-2-imidazolinyl, 2-carbamoylimidazolidinyl,4-carbamoylimidazolidinyl, 5-carbamoylimidazolidinyl,3-carbamoyl-2-pyrazolinyl, 4-carbamoyl-2-pyrazolinyl,5-carbamoyl-2-pyrazolinyl, 3-carbamoylpyrazolidinyl,4-carbamoylpyrazolidinyl, 5-carbamoylpyrazolidinyl,2-carbamoyl-1,2-dihydropyridyl, 3-carbamoyl-1,2-dihydropyridyl,4-carbamoyl-1,2-dihydropyridyl, 2,6-dicarbamoyl-1,2-dihydropyridyl,3,4-dicarbamoylpiperidinyl, 2,4,6-tricarbamoyl-1,2-dihydropyridyl,4-carbamoyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricarbamoyl-1,2,3,4-tetrahydropyridyl,3,4-dicarbamoyl-1,2,3,4-tetrahydropyridyl, 3,4-dicarbamoylpiperazinyl,2-carboxypyrrolidinyl, 3-carboxypyrrolidinyl, 4-carboxypiperidinyl,3-carboxypiperidinyl, 2-carboxypiperidinyl, 4-carboxypiperazinyl,3-carboxypiperazinyl, 2-carbboxypiperazinyl, 3-carboxymorpholino,2-carboxymorpholino, 2-carboxypyrrolyl, 3-carboxypyrrolyl,2-carboxyimidazolyl, 4-carboxyimidazolyl, 5-carboxyimidazolyl,3-carboxy-1,2,4-triazolyl, 5-carboxy-1,2,4-triazolyl,2-carboxy-1,2,4-triazolyl, 5-carboxypyrazolyl, 3-carboxypyrazolyl,2-carboxy-2-pyrrolinyl, 3-carboxy-2-pyrrolinyl, 4-carboxy-2-pyrrolinyl,5-carboxy-2-pyrrolinyl, 2-carboxy-2-imidazolyl,5-carboxy-1,2,3,4-tetrazolyl, 4-carboxy-2-imidazolinyl,5-carboxy-2-imidazolyl, 2-carboxyimidazolidinyl,4-carboxyimidazolidinyl, 5-carboxyimidazolidinyl,5-carboxy-2-pyrazolinyl, 3-carboxypyrrazolidinyl,4-carboxypyrrazolidinyl, 5-carboxypyrrazolidinyl,2-carboxy-1,2-dihydropyridyl, 3-carboxy-1,2-dihydropyridyl,4-carboxy-1,2-dihydropyridyl, 2,6-dicarboxy-1,2-dihydropyridyl,3,4-dicarboxypiperidinyl, 2,4,6-tricarboxy-1,2-dihydropyridyl,4-carboxy-1,2,3,4-tetrahydropyridyl,3,4,5-tricarboxy-1,2,3,4-tetrahydropyridyl,3,4-dicarboxy-1,2,3,4-tetrahydropyridyl, 3,4-dicarboxypiperazinyl,2-cyclopropylpyrrolidinyl, 3-cyclopropylpyrrolidinyl,4-cyclopropylpiperidinyl, 3-cyclopropylpiperidinyl,2-cyclopropylpiperidinyl, 4-cyclopropylpiperazinyl,3-cyclopropylpiperazinyl, 2-cyclopropylpiperazinyl,3-cyclopropylmorpholino, 2-cyclopropylmorpholino, 2-cyclopropylpyrrolyl,3-cyclopropylpyrrolyl, 2-cyclopropylimidazolyl, 4-cyclopropylimidazolyl,5-cyclopropylimidazolyl, 3-cyclopropyl-1,2,4-triazolyl,5-cyclopropyl-1,2,4-triazolyl, 2-cyclopropyl-1,2,4-triazolyl,5-cyclopropylpyrazolyl, 3-cyclopropylpyrazolyl,2-cyclopropyl-2-pyrrolinyl, 3-cyclopropyl-2-pyrrolinyl,4-cyclopropyl-2-pyrrolinyl, 5-cyclopropyl-2-pyrrolinyl,2-cyclopropyl-2-imidazolyl, 5-cyclopropyl-1,2,3,4-tetrazolyl,4-cyclopropyl-2-imidazolinyl, 5-cyclopropyl-2-imidazolyl,2-cyclopropylimidazolidinyl, 4-cyclopropylimidazolidinyl,5-cyclopropylimidazolidinyl, 5-cyclopropyl-2-pyrazolinyl,3-cyclopropylpyrazolidinyl, 4-cyclopropylpyrazolidinyl,5-cyclopropylpyrazolidinyl, 2-cyclopropyl-1,2-dihydropyridyl,3-cyclopropyl-1,2-dihydropyridyl, 4-cyclopropyl-1,2-dihydropyridyl,2,6-dicyclopropyl-1,2-dihydropyridyl, 3,4-dicyclopropylpiperidinyl,2,4,6-tricyclopropyl-1,2-dihydropyridyl,4-cyclopropyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricyclopropyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclopropyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclopropylpiperazinyl, 2-cyclobutylpyrrolidinyl,3-cyclobutylpyrrolidinyl, 4-cyclobutylpiperidinyl,3-cyclobutylpiperidinyl, 2-cyclobutylpiperidinyl,4-cyclobutylpiperazinyl, 3-cyclobutylpiperazinyl,2-cyclobutylpiperazinyl, 3-cyclobutylmorpholino, 2-cyclobutylmorpholino,2-cyclobutylpyrrolyl, 3-cyclobutylpyrrolyl, 2-cyclobutylimidazolyl,4-cyclobutylimidazolyl, 5-cyclobutylimidazolyl,3-cyclobutyl-1,2,4-triazolyl, 5-cyclobutyl-1,2,4-triazolyl,2-cyclobutyl-1,2,4-triazolyl, 5-cyclobutylpyrazolyl,3-cyclobutylpyrazolyl, 2-cyclobutyl-2-pyrrolinyl,3-cyclobutyl-2-pyrrolinyl, 4-cyclobutyl-2-pyrrolinyl,5-cyclobutyl-2-pyrrolinyl, 2-cyclobutyl-2-imidazolyl,5-cyclobutyl-1,2,3,4-tetrazolyl, 4-cyclobutyl-2-imidazolinyl,5-cyclobutyl-2-imidazolyl, 2-cyclobutylimidazolidinyl,4-cyclobutylimidazolidinyl, 5-cyclobutylimidazolidinyl,5-cyclobutyl-2-pyrazolinyl, 3-cyclobutylpyrazolidinyl,4-cyclobutylpyrazolidinyl, 5-cyclobutylpyrazolidinyl,2-cyclobutyl-1,2-dihydropyridyl, 3-cyclobutyl-1,2-dihydropyridyl,4-cyclobutyl-1,2-dihydropyridyl, 2,6-dicyclobutyl-1,2-dihydropyridyl,3,4-dicyclobutylpiperidinyl, 2,4,6-tricyclobutyl-1,2-dihydropyridyl,4-cyclobutyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricyclobutyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclobutyl-1,2,3,4-tetrahydropyridyl, 3,4-dicyclobutylpiperazinyl,2-cyclopentylpyrrolidinyl, 3-cyclopentylpyrrolidinyl,4-cyclopentylpiperidinyl, 3-cyclopentylpiperidinyl,2-cyclopentylpiperidinyl, 4-cyclopentylpiperazinyl,3-cyclopentylpiperazinyl, 2-cyclopentylpiperazinyl,3-cyclopentylmorpholino, 2-cyclopentylmorpholino, 2-cyclopentylpyrrolyl,3-cyclopentylpyrrolyl, 2-cyclopentylimidazolyl, 4-cyclopentylimidazolyl,5-cyclopentylimidazolyl, 3-cyclopentyl-1,2,4-triazolyl,5-cyclopentyl-1,2,4-triazolyl, 2-cyclopentyl-1,2,4-triazolyl,5-cyclopentylpyrazolyl, 3-cyclopentylpyrazolyl,2-cyclopentyl-2-pyrrolinyl, 3-cyclopentyl-2-pyrrolinyl,4-cyclopentyl-2-pyrrolinyl, 5-cyclopentyl-2-pyrrolinyl,2-cyclopentyl-2-imidazolyl, 5-cyclopentyl-1,2,3,4-tetrazolyl,4-cyclopentyl-2-imidazolinyl, 5-cyclopentyl-2-imidazolyl,2-cyclopentylimidazolidinyl, 4-cyclopentylimidazolidinyl,5-cyclopentylimidazolidinyl, 5-cyclopentyl-2-pyrazolinyl,3-cyclopentylpyrazolidinyl, 4-cyclopentylpyrazolidinyl,5-cyclopentylpyrazolidinyl, 2-cyclopentyl-1,2-dihydropyridyl,3-cyclopentyl-1,2-dihyropyridyl, 4-cyclopentyl-1,2-dihyropyridyl,2,6-dicyclopentyl-1,2-dihydropyridyl, 3,4-dicyclopentylpiperidinyl,2,4,6-tricyclopentyl-1,2-dihydropyridyl,4-cyclopentyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricyclopentyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclopentyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclopentylpiperazinyl, 2-cyclohexylpyrrolidinyl,3-cyclohexylpyrrolidinyl, 4-cyclohexylpiperidinyl,3-cyclohexylpiperidinyl, 2-cyclohexylpiperidinyl,4-cyclohexylpiperazinyl, 3-cyclohexylpiperazinyl,2-cyclohexylpiperazinyl, 3-cyclohexylmorpholino, 2-cyclohexylmorpholino,2-cyclohexylpyrrolyl, 3-cyclohexylpyrrolyl, 2-cyclohexylimidazolyl,4-cyclohexylimidazolyl, 5-cyclohexylimidazolyl,3-cyclohexyl-1,2,4-triazolyl, 5-cyclohexyl-1,2,4-triazolyl,2-cyclohexyl-1,2,4-triazolyl, 5-cyclohexylpyrazolyl,3-cyclohexylpyrazolyl, 2-cyclohexyl-2-pyrrolinyl,3-cyclohexyl-2-pyrrolinyl, ⁴ -cyclohexyl-2-pyrrolinyl,5-cyclohexyl-2-pyrrolinyl, 2-cyclohexyl-2-imidazolyl,5-cyclohexyl-1,2,3,4-tetrazolyl, 4-cyclohexyl-2-imidazolinyl,5-cyclohexyl-2-imidazolyl, 2-cyclohexylimidazolidinyl,4-cyclohexylimidazolidinyl, 5-cyclohexylimidazolidinyl,5-cyclohexyl-2-pyrazolinyl, 3-cyclohexylpyrazolidinyl,4-cyclohexylpyrazolidinyl, 5-cyclohexylpyrazolidinyl,2-cyclohexyl-1,2-dihydropyridyl, 3-cyclohexyl-1,2-dihydropyridyl,4-cyclohexyl-1,2-dihydropyridyl, 2,6-dicyclohexyl-1,2-dihydropyridyl,3,4-dicyclohexylpiperidinyl, 2,4,6-tricyclohexyl-1,2-dihydropyridyl,4-cyclohexyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricyclohexyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclohexyl-1,2,3,4-tetrahydropyridyl, 3,4-dicyclohexylpiperazinyl,2-cycloheptylpyrrolidinyl, 3-cycloheptylpyrrolidinyl,4-cycloheptylpiperidinyl, 3-cycloheptylpiperidinyl,2-cycloheptylpiperidinyl, 4-cycloheptylpiperazinyl,3-cycloheptylpiperazinyl, 2-cycloheptylpiperazinyl,3-cycloheptylmorpholino, 2-cycloheptylmorpholino, 2-cycloheptylpyrrolyl,3-cycloheptylpyrrolyl, 2-cycloheptylimidazolyl, 4-cycloheptylimidazolyl,5-cycloheptylimidazolyl, 3-cycloheptyl-1,2,4-triazolyl,5-cycloheptyl-1,2,4-triazolyl, 2-cycloheptyl-1,2,4-triazolyl,5-cycloheptylpyrazolyl, 3-cycloheptylpyrazolyl,2-cycloheptyl-2-pyrrolinyl, 3-cycloheptyl-2-pyrrolinyl,4-cycloheptyl-2-pyrrolinyl, 5-cycloheptyl-2-pyrrolinyl,2-cycloheptyl-2-imidazolyl, 5-cycloheptyl-1,2,3,4-tetrazolyl,4-cycloheptyl-2-imidazolinyl, 5-cycloheptyl-2-imidazolyl,2-cycloheptylimidazolidinyl, 4-cycloheptylimidazolidinyl,5-cycloheptylimidazolidinyl, 5-cycloheptyl-2-pyrazolinyl,3-cycloheptylpyrazolidinyl, 4-cycloheptylpyrazolidinyl,5-cycloheptylpyrazolidinyl, 2-cycloheptyl-1,2-dihydropyridyl,3-cycloheptyl-1,2-dihydropyridyl, 4-cycloheptyl-1,2-dihydropyridyl,2,6-dicycloheptyl-1,2-dihydropyridyl, 3,4-dicycloheptylpiperidinyl,2,4,6-tricycloheptyl-1,2-dihydropyridyl,4-cycloheptyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricycloheptyl-1,2,3,4-tetrahydropyridyl,3,4-dicycloheptyl-1,2,3,4-tetrahydropyridyl,3,4-dicycloheptylpiperazinyl, 2-cyclooctylpyrrolidinyl,3-cyclooctylpyrrolidinyl, 4-cyclooctylpiperidinyl,3-cyclooctylpiperidinyl, 2-cyclooctylpiperidinyl,4-cyclooctylpiperazinyl, 3-cyclooctylpiperazinyl,2-cyclooctylpiperazinyl, 3-cyclooctylmonopholino,2-cyclooctylmonopholino, 2-cyclooctylpyrrolyl, 3-cyclooctylpyrrolyl,2-cyclooctylimidazolyl, 4-cyclooctylimidazolyl, 5-cyclooctylimidazolyl,3-cyclooctyl-1,2,4-triazolyl, 5-cyclooctyl-1,2,4-triazolyl,2-cyclooctyl-1,2,4-triazolyl, 5-cyclooctylpyrazolyl,3-cyclooctylpyrazolyl, 2-cyclooctyl-2-pyrrolinyl,3-cyclooctyl-2-pyrrolinyl, 4-cyclooctyl-2-pyrrolinyl,5-cyclooctyl-2-pyrrolinyl, 2-cyclooctyl-2-imidazolyl,5-cyclooctyl-1,2,3,4-tetrazolyl, 4-cyclooctyl-2-imidazolinyl,5-cyclooctyl-2-imidazolyl, 2-cyclooctylimidazolidinyl,4-cyclooctylimidazolidinyl, 5-cyclooctylimidazolidinyl,5-cyclooctyl-2-pyrazolinyl, 3-cyclooctylpyrazolidinyl,4-cyclooctylpyrazolidinyl, 5-cyclooctylpyrazolidinyl,2-cyclooctyl-1,2-dihydropyridyl, 3-cyclooctyl-1,2-dihydropyridyl,4-cyclooctyl-1,2-dihydropyridyl, 2,6-dicyclooctyl-1,2-dihydropyridyl,3,4-dicyclooctylpiperidinyl, 2,4,6-tricyclooctyl-1,2-dihydropyridyl,4-cyclooctyl-1,2,3,4-tetrahydropyridyl,3,4,5-tricyclooctyl-1,2,3,4-tetrahydropyridyl,3,4-dicyclooctyl-1,2,3,4-tetrahydropyridyl, 3,4-dicyclooctylpiperazinyl,4-phenylpiperazinyl, 5-(3-chlorophenyl)-1,2,3,4-tetrazolyl,4-(3-chlorophenyl)piperazinyl, 4-(4-bromophenyl)piperidinyl,3-(2-iodophenyl)pyrrolidinyl, 3-(4-fluorophenyl)morpholino,3-(2-chlorophenyl)-pyrrolyl, 3-(3-bromophenyl)imidazolyl,3-(4-iodophenyl)-1,2,4-triazolyl, 2-(2-fluorophenyl)-1,3,4-triazolyl,3-(2,3-dichlorophenyl)pyrazolyl, 4-(3,4-dibromophenyl)-2-pyrrolinyl,2-(2,5-diiodophenyl)-2-imidazolinyl,3-(3,4-difluorophenyl)imidazolidinyl,3-(2,4,6-trichlorophenyl)-2-pyrazolinyl,4-(4-chlorophenyl)pyrazolidinyl, 4-(2-bromophenyl)-1,2-dihydropyridyland 4-(2-chloro-4-bromophenyl)-1,2,3,4-tetrahydropyridyl groups can beexemplified.

As to the lower alkanoyloxy-substituted lower alkyl group, a straightchain- or branched chain-alkyl group having 1 to 6 carbon atoms beingsubstituted with a straight chain- or branched chain-alkanoyloxy grouphaving 2 to 6 carbon atoms, such as acetyloxymethyl,2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl,4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl,6-acetyloxyhexyl, 6-tert-butylcarbonyloxyhexyl,1,1-dimethyl-2-hexanoyloxyethyl and 2-methyl-3-acetyloxypropyl groupscan be exemplified.

As to the cyano group-substituted lower alkyl group, a cyanoalkyl groupin which the alkyl moiety is a straight chain- or branched chain-alkylgroup having 1 to 6 carbon atoms, such as cyanomethyl, 2-cyanoethyl,3-cyanopropyl, 1-methyl-2-cyanoethyl, 1-cyanoethyl, 4-cyanobutyl,1,1-dimethyl-2-cyanoethyl, 5-cyanopentyl, 6-cyanohexyl,2-methyl-3-cyanopropyl and 4-methyl-1-cyanopentyl groups can beexemplified.

As to the carboxy-substituted lower alkyl group, a carboxyalkyl group inwhich the alkyl moiety is a straight chain- or branched chain-alkylgroup having 1 to 6 carbon atoms, such as carboxymethyl, 2-carboxyethyl,1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl,6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyland 4-methyl-1-carboxypentyl groups can be exemplified.

As to the lower alkanoyl group which may have halogen atom(s), astraight chain- or branched chain-alkanoyl group having 1 to 6 carbonatoms which may have 1 to 3 halogen atoms as the substituents, such asformyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,tert-butylcarbonyl, hexanoyl, 2,2,2-trifluoroacetyl,2,2,2-trichloroacetyl, 2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl,2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl,3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloropropionyl,4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl,3-chloro-2-methylpropionyl, 6-bromohexanoyl and 5,6-dibromohexanoylgroups can be exemplified.

As to the carbamoyl-substituted lower alkyl group, a carbamoylalkylgroup in which the alkyl moiety is a straight chain- or branchedchain-alkyl group having 1 to 6 carbon atoms, such as carbamoylmethyl,2-carbamoylethyl, 1-carbamoylethyl, 3-carbamoylpropyl, 4-carbamoylbutyl,5-carbamoylpentyl, 6-carbamoylhexyl, 1,1-dimethyl-2-carbamoylethyl and2-methyl-3-carbamoylpropyl groups can be exemplified.

Among the cyclic amide derivatives of the present invention, when m is1, then R³ may preferably be bonded at any one of 5 to 8 position; andwhen m is 0, then R³ may preferably be bonded at any one of 4 to 7position. Further, as to preferable compounds of the present invention,those having that R² is a hydroxyl group; Z is a methylene group; m is1; R¹ is an alkenyl group, a cycloalkyl-lower alkyl group or aphenyl-lower alkyl group having one substituent selected from the groupconsisting of a lower alkenyloxy group and an alkoxy group; n is 2; R²is bonded at 6-position and R³ are bonded at 5- and 7-positions can beexemplified.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The cyclic amide derivatives of the present invention can be preparedeasily by methods as shown in various reaction formulae as follows.

Reaction formula-1 ##STR8##

In the Reaction formula-1, R², R³,n, m and Z are the same as definedabove; R^(1a) is the same as defined above, except a hydrogen atom; X isa halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxygroup.

As to the lower alkylsulfonyloxy group, concretely, methylsulfonyloxy,ethyisulfonyloxy, isopropylsulfonyloxy, propylsulfonyloxy,butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy andhexylsulfonyloxy groups can be exemplified. As to the arylsulfonyloxygroup, concretely, phenylsulfonyloxy, 4-methylphenylsulfonyloxy,2-methyiphenylsulfonyloxy, 4-nitrophenylsulfonyloxy,4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy andα-naphthylsulfonyloxy groups can be exemplified.

In the above-mentioned Reaction formula-1, the reaction of a compoundrepresented by the general formula (2) with a compound represented bythe general formula (3) can be easily carried out without solvent or ina suitable inert solvent. Ratio of the used amount of a compound of thegeneral formula (2) to the used amount of a compound of the generalformula (3) is not specifically restricted and can be selected from awide range. Generally, an equimolar to an excess quantity, preferably anequimolar to 5 times the molar quantity of the latter may be used to themolar quantity of the former. As to the inert solvent to be used in thereaction, aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as dimethyl ether, diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and ethylene glycol; polar solvents such asdimethyl sulfoxide, dimethylformamide, hexamethylphosphoryl triamide andacetonitrile; as well as mixed solvent thereof can be exemplified.

The above reaction can advantageously be carried out by using a basicmaterial as the dehydrohalogenation agent. As to the dehydrohalogenationagent to be used, alkali metals, such as metallic sodium and metallicpotassium; alkali metal amides, such as sodium amide and potassiumamide; sodium hydride and sodium hydroxide can be exemplified. The abovereaction can also be carried out by adding, as the reaction accelerator,metal iodide compound for example, potassium iodide or sodium iodide;copper powder or copper halide to the reaction system. The reaction canbe carried out generally at about 0 to 200° C., preferably at roomtemperature to 100° C. and is completed in about 1 to 24 hours.

Among the compounds represented by the general formula (1a), whereinR^(1a) is a hydroxy-substituted alkyl group can be prepared by reating acompound represented by general formula (2) with atetrahydropyranyloxy-substituted alkyl halide compound under thereaction condition similar to that employed in the reaction between acompound (2) and a compound (3), then thus obtained compound (1a)wherein R^(1a) is tetrahydropyranyloxy-substituted alkyl group ishydrolyzed under the condition similar to that employed in thehydrolysis in Reaction formula-7 as shown later.

In addition to the above, the compound (1a) wherein R^(1a) is aphenyl-lower alkyl group having a group represented by the formula:##STR9## can be prepared by reacting a compound (2) with a phenyl-loweralkyl halide compound having halogenated methyl group as thesubstituent, under the reaction condition similar to that employed inthe above-mentioned reaction of a compound (2) with a compound (3). Inthis case, 0.1 to 1.5 times the molar quantity of a phenyl-lower alkylhalide compound, having halogenated methyl group as the substituent, maypreferably be used to a molar quantity of a compound (2).

Reaction formula-2 ##STR10##

In the Reaction formula-2, R¹, R³, n, m and Z are the same as definedabove; R^(2a) is a lower alkenyl group, a phenyl-lower alkenyl group, acycloalkenyl group, a pyridyl group, a lower alkanoyl group which mayhave carboxy group(s); X¹ is a halogen atom.

In the above-mentioned Reaction formula-2, the reaction of a compoundrepresented by the general formula (1b) with a compound represented bythe general formula (4) can be carried out without solvent or in aninert solvent, in the absence of or in the presence of a basic compound.Ratio of the used amount of the compound of the general formula (1b) tothe used amount of the compound of the general formula (4) is notspecifically restricted, and generally an equimolar to an excessquantity, preferably an equimolar to 5 times the molar quantity of thelatter may be used to the former. As to the inert solvent to be used,water; aromatic hydrocarbons such as benzene, toluene and xylene; etherssuch as dimethyl ether, diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and diethylene glycol; halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride; lower alcoholsuch as methanol, ethanol, isopropanol, butanol, tert-butanol; ketonessuch as methyl ethyl ketone; acetic acid; ethyl acetate; acetone;acetonitrile; pyridine; dimethyl sulfoxide; dimethylformamide andhexamethylphosphoryl triamide; and mixed solvents thereof can beexemplified. As to the basic materials, carbonate such as sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate; metal hydroxides such as sodium hydroxide, potassiumhydroxide; sodium hydride; metallic potassium and metallic sodium;sodium amide; metal alcoholates such as sodium methylate and sodiumethylate; organic bases such as pyridine, N-ethyldiisopropylamine,dimethylaminopyridine, triethylamine, tripropylamine, 1,5-diazabicyclo4.3.0!-5-nonene (DBN), 1,8-diazabicyclo 5.4.0!-7-undecene (DBU) and1,4-diazabicyclo 2.2.2!octane (DABCO) can be exemplified. This reactioncan be carried out, generally at about room temperature to 200° C.,preferably at about room temperature to 100° C., and is generallycompleted in 1 to 24 hours. Into the reaction system, an alkali metalhalide, such as sodium iodide or potassium iodide may be added.

Reaction formula-3 ##STR11##

In the Reaction formula-3, R¹, R³, m and Z are the same as definedabove; R^(2b) and R^(2c) are each a lower alkenyl group, respectively; pis 0, 1 or 2.

The reaction introducing a compound represented by the general formula(1d) to a compound represented by the general formula (1e) is called asClaisen rearrangement, which is carried out without solvent or in aninert solvent, and generally under temperature condition at 100° to 250°C., preferably at 150° to 250° C., and is completed in 1 to 24 hours. Asto the inert solvent to be used, solvents having higher-boiling point,such as diglyme, ethylene glycol, N,N-dimethylaniline,N,N,-diethylaniline, tetralin, decalin, dimethylformamide,tetrahydronaphthalene and diphenyl ether can be exemplified. Theabove-mentioned reaction can advantageously be carried out in an inertgas atmosphere. As to the inert gas, nitrogen gas and argon gas can beused.

Reaction formula-4 ##STR12##

In the Reaction formula-4, R², R³, n, m, Z, A, X¹, R⁴ and R⁵ are thesame as defined above.

The reaction of a compound represented by the general formula (1f) witha compound represented by the general formula (5) can be easily carriedout without a solvent or in an inert solvent. Ratio of the used amountsof a compound of the general formula (1f) to a compound of the generalformula (5) is not specifically restricted, and can be selected from awide range. Generally, an equimolar to an excess quantity, preferablyably an equimolar to 5 times the molar quantity of the latter may beused to a molar quantity of the former. As to the inert solvent to beused, aromatic hydrocarbons such as benzene, toluene and xylene; etherssuch as dimethyl ether, diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and diethylene glycol; halogenated hydrocarbonssuch as dichloromethane, chloroform and carbon tetrachloride; loweralcohols such as methanol, ethanol, isopropanol, butanol andtert-butanol; ketones such as methyl ethyl ketone; acetic acid, ethylacetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide,dimethylformamide, and hexamethylphosphoryl triamide; and mixed solventsthereof can be exemplified. The above-mentioned reaction canadvantageously be carried out by using basic material. As to the basicmaterial, carbonates such as sodium carbonate, potassium carbonate,sodium hydrogen carbonate and potassium hydrogen carbonate; metalhydroxides such as sodium hydroxide, and potassium hydroxide; sodiumhydride, metallic potassium, metallic sodium, sodium amide, alkali metalalcoholate such as sodium methylate and sodium ethylate; organic basiccompounds such as pyridine, N-ethyldiisopropylamine,dimethylaminopyridine, triethylamine, tripropylamine, DBN, DBU and DABCOcan be exemplified. The reaction is carried out generally at about roomtemperature to 200° C., preferably at about room temperature to 100° C.,and generally the reaction is completed in about 1 to 24 hours. Into thereaction system, an alkali metal halide, such as sodium iodide orpotassium iodide may be added.

Reaction formula-5 ##STR13##

In the Reaction formula-5, R², R³, n, m, Z and A are the same as definedabove.

In the above-mentioned Reaction formula-5, the reaction for introducinga compound represented by the general formula (1h) to a compoundrepresented by the general formula (1i) can be carried out by reacting acompound of the general formula (1h) with hydrazin monohydrate withoutsolvent or in an inert solvent. Ratio of the used amounts of compound(1h) to hydrazin monohydrate is not specifically restricted, and can beselected from a wide range, and generally an equimolar to an excessquantity, preferably an equimolar to 5 times the molar quantity of thelatter may be used to the molar quantity of the former. As to the inertsolvent to be used, aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as tetrahydrofuran, dioxane, diethylene glycoldimethyl ether, diethyl ether, diisopropyl ether and ethylene glycol;lower alcohols such as methanol, ethanol, isopropanol and butanol;acetic acid, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide,dimethylformamide, hexamethylphosphoryl triamide can be exemplified. Thereaction is generally carried out at about room temperature to 150° C.,preferably at room temperature to 100° C., and the reaction is generallycompleted in about 1 to 24 hours.

Reaction formula-6 ##STR14##

In the Reaction formula-6, R², R³, n, m, Z. X¹ and A are the same asdefined above; R^(4a) is a phenylsulfonyl group which may have loweralkyl group(s) as substituent(s) in the phenyl ring, a loweralkoxy-lower alkyl group, a lower alkyl group, a hydroxylgroup-substituted lower alkyl group, a lower alkoxycarbonylgroup-substituted lower alkyl group or a carboxy-substituted lower alkylgroup; R^(4b) is a lower alkanoyl group which may have halogen atom(s)as substituent(s); R^(5a) is a hydrogen atom, a carbamoyl group, a loweralkanoyl group which may have halogen atom(s), a phenylsulfonyl groupwhich may have lower alkyl group(s) as substituent(s) in the phenylring, a lower alkoxy-lower alkyl group, a lower alkyl group, a hydroxylgroup-substituted lower alkyl group, a lower alkoxycarbonyl-substitutedlower alkyl group or a carboxy-substituted lower alkyl group; and M isalkali metal such as sodium or potassium.

The reaction of a compound represented by the general formula (1j) witha compound represented by the general formula (6) is carried out undercondition similar to that employed in the reaction of a compound of (1f)with a compound of (5) as disclosed in the Reaction formula-4.

The reaction of a compound of the general formula (1j) with a compoundof the general formula (9) is carried out in the absence or presence ofan acid, in a suitable solvent. As to the acid to be used, organic acidssuch as acetic acid and trifluoroacetic acid; mineral acids such ashydrochloric acid and sulfuric acid can be exemplified. As to thesolvent to be used, alcohols such as methanol, ethanol, propanol,butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve;pyridine; acetone; water; halogenated hydrocarbons such asdichloromethane, dichloroethane and chloroform; aromatic hydrocarbonssuch as benzene, toluene and xylene; ethers such as dimethoxyethane,tetrahydrofuran, diethyl ether and diisopropyl ether; esters such asethyl acetate and methyl acetate; aprotic polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile andhexamethylphosphory triamide; and mixed solvents thereof can beexemplified. The amount of compound (9) may be used in generally, anequimolar quantity to an excess quantity, preferably an equimolarquantity to about 5 times the molar quantity to the molar quantity of acompound of (1j). The reaction is generally carried out at 0° to 150°C., preferably at room temperature to 100° C., and generally thereaction is completed in about 10 minutes to 15 hours.

The reaction of a compound of the general formula (1j) with a compoundrepresented by the general formula (7) or (8) is carried out in thepresence of a basic compound, in a suitable solvent. As to the basiccompound to be used, known basic compounds can selected from a widerange, thus organic bases such as triethylamine, trimethylamine,pyridine, dimethylaniline, DBN, DBU and DABCO; inorganic bases such aspotassium carbonate, sodium carbonate, potassium hydrogen carbonate,sodium hydrogen carbonate; sodium hydroxide, potassium hydroxide, sodiumhydride and potassium hydride can be exemplified. As to the solvent tobe used, alcohols such as methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve; pyridine;acetone; water; halogenated hydrocarbons such as chloromethane,dichhloroethane and chloroform; aromatic hydrocarbons such as benzene,toluene and xylene; ethers such as dimethoxyethane, tetrahydrofuran,diethyl ether and diisopropyl ether; esters such as ethyl acetate andmethyl acetate; aprotic polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and hexamethylphosphoryl triamide canbe exemplified. The ratio of used amounts of a compound of the generalformula (1j) to a compound of the general formula (7) or (8) is notspecifically restricted, and can be selected from a wide range,generally an equimolar quantity to an excess quantity, preferably anequimolar to 5 times the molar quantity of the latter may be used to themolar quantity of the former. The reaction is generally carried out at-20° to about 180° C., preferably at 0° to about 150° C., and thereaction is generally completed in about 5 minutes to 30 hours.

Reaction formula-7 ##STR15##

In the Reaction formula-7, R², R³, n, m and Z are the same as definedabove; R^(1b) is a lower alkoxycarbonyl-substituted lower alkyl group, alower alkanoyloxy-lower alkyl group or a group of the formula: ##STR16##(wherein A and R^(5a) are the same as defined above; and R^(4c) is alower alkoxycarbonyl-substituted lower alkyl group); R^(1c) is acarboxy-substituted lower alkyl group, a hydroxyl group-substitutedlower alkyl group or a group of the formula: ##STR17## (wherein A andR^(5a) are the same as defined above; and R^(4d) is acarboxy-substituted lower alkyl group); and R^(1d) is acarbamoyl-substituted lower alkyl group.

In the Reaction formula-7, the hydrolysis reaction of a compoundrepresented by the general formula (1n) can be carried out withoutsolvent or in a suitable inert solvent, in the presence of an acid orbasic compound. As to the solvent to be used, water; a lower alcoholsuch as methanol, ethanol and isopropanol; ketones such as acetone andmethyl ethyl ketone; ethers such as dioxane, tetrahydrofuran andethylene glycol dimethyl ether; fatty acids such as acetic acid andformic acid; dimethylformamide; and mixed solvents thereof can beexemplified. As to the acid, mineral acids such as hydrochloric acid,sulfuric acid, hydrobromic acid, phosphoric acids and polyphosphoricacids; organic acids such as formic acid, acetic acid and aromaticsulfonic acids can be exemplified. Furthermore, as to the basiccompounds, metal carbonates such as sodium carbonate and potassiumcarbonate; metal hydroxides such as sodium hydroxide, potassiumhydroxide and calcium hydroxide; sodium acetate can be exemplified.Generally, the reaction is carried out at room temperature to about 150°C., preferably at room temperature to about 100° C. and is completedgenerally in about 10 minute to 25 hours. Ratio of used amount of acompound (1n) to the amount of acid or basic compound is notspecifically restricted, and generally an equimolar quantity to anexcess quantity, preferably an equimolar quantity to 5 times the molarquantity of the latter may be used to the molar quantity of the former.

Among the compound represented by the general formula (1o),esterification reaction of the compound wherein R^(1c) is acarboxy-substituted lower alkyl group ##STR18## (wherein A, R^(4d) andR^(5a) are the same as defined above) can be carried out by reacting acompound of the formula (1o) with an alcohol such as methanol, ethanolor isopropanol, generally at 0° to 150° C., preferably at 50° to 100°C., for about 5 minutes to 10 hours, in the presence of a mineral acidsuch as hydrochloric acid or sulfuric acid; or halogenating agent suchas thionyl chloride, phosphorus oxychloride, phosphorus pentachloride orphosphorus trichloride.

Among the compounds represented by the general formula (1n), a compoundhaving a lower alkoxycarbonyl substituted-lower alkyl group as toR^(1b), or among the compounds represented by the general formula (1o),a compound having carboxy-substituted lower alkyl group as to R^(1c) thereaction with ammonia (10) can be carried out easily in a suitable inertsolvent. Ratio of the used amount of a compound of the general formula(1n) or (1o) to the used amount of ammonia (10) is not specificallyrestricted and can be selected from a wide range, and generally anequimolar quantity to an excess quantity, preferably 2 to 10 times themolar quantity of the latter may be used to the molar quantity of theformer. As to the inert solvent, water is generally used, and loweralcohols such as methanol, ethanol and isopropanol; ethers such asdioxane, ethylene glycol, tetrahydrofuran and ethylene glycol dimethylether; dimethyl sulfoxide, dimethylformamide, hexamethylphosphoryltrimide, pyridine, acetone, acetonitrile and mixed solvents thereof canbe exemplified. The reaction is carried out, generally at roomtemperature to 150° C., preferably at room temperature to 100° C., andgenerally the reaction is completed in about 1 to 30 hours.

Reaction formula-8 ##STR19##

In the Reaction formula-8, R¹, R³, n, m and Z are the same as definedabove.

The reaction of a compound represented by the general formula (1q) witha compound represented by the general formula (11) is carried out, inthe presence of an acid, in a suitable solvent or without solvent. As tothe acid to be used, organic acids such as acetic acid, trifluoroaceticacid, formic acid and aromatic sulfonic acid; and mineral acids such ashydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acidscan be exemplified. As to the solvent to be used, alcohols such asmethanol, ethanol, propanol, butanol and 3-methoxy-1-butanol;halogenated hydrocarbons such as chloroform, dichloromethane anddichloroethane; aromatic hydrocarbon such as benzene, p-chlorobenzene,toluene and xylene; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran and dimethoxyethane; esters such as methyl acetate andethyl acetate; aprotic polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and hexamethylphosphoryl triamide;pyridine; acetone; water; and mixed solvents thereof can be exemplified.

Used amount of a compound (11) may be generally at least an equimolarquantity, preferably an equimolar quantity to an excess quantity to themolar quantity of a compound (1q). The reaction is carried out generallyat room temperature to 150° C., preferably at room temperature to around100° C., and the reaction is generally completed in about 10 minutes to12 hours.

A compound of the general formula (1q) can be obtained by heating thecompound of the general formula (1r) in the presence of a suitable acid,and in a suitable solvent or without solvent, generally at roomtemperature to 150° C., preferably at room temperature to around 100° C.for about 10 minutes to 12 hours. As to the acid to be used, organicacids such as acetic acid, trifluoroacetic acid, formic acid andaromatic sulfonic acid; and mineral acids such as hydrochloric acid,sulfuric acid, hydrobromic acid and phosphoric acids can be exemplified.As to the solvent to be used, alcohols such as methanol, ethanol,propanol, butanol and 3-methoxy-1-butanol; halogenated hydrocarbons suchas chloroform, dichloromethane and dichloroethane; aromatic hydrocarbonsuch as benzene, p-chlorobenzene, toluene and xylene; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane;esters such as methyl acetate and ethyl acetate; aprotic polar solventssuch as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile andhexamethyl-phosphoryl triamide; pyridine; acetone; water; and mixedsolvents thereof can be exemplified.

Reaction formula -9 ##STR20##

In the reaction formula -9, R², R³, n, m, z, A and X¹ are the same asdefined above; R^(a), R^(b) and R^(c) are each the same or different,and is a lower alkoxy group or a hydroxyl group.

The reaction of a compound represented by the general formula (1s) witha compound represented by the general formula (12) can easily be carriedout without solvent or in a suitable inert solvent. Ratio of the usedamounts of a compound of the general formula (1s) to a compound of thegeneral formula (12) is not specifically restricted, and can be selectedfrom a wide range, generally an equimolar quantity to an excessquantity, preferably an equimolar quantity to 5 times the molar quantityof the latter may be used to the molar quantity of the former. As to theinert solvent to be used aromatic hydrocarbon such as benzene, tolueneand xyiene; ethers such as dimethyl ether, diethyl ether, diisopropylether, tetrahydrofuran, dioxane and diethylene glycol; halogenatedhydrocarbons such as dichloromethane, chloroform and carbontetra-chloride; lower alcohols such as methanol, ethanol, isopropanol,butanol and tert-butanol; ketones such as methyl ethyl ketone; aceticacid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide and hexamethylphosphoryl triamide; andmixed solvents thereof can be exemplified. The above-mentioned reactionis carried out advantageously by using a basic material. As to the basicmaterials, carbonates such as sodium carbonate, potassium carbonate,sodium hydrogen carbonate and potassium hydrogen carbonate; metalhydroxide such as sodium hydroxide and potassium hydroxide; sodiumhydride; metallic potassium, metallic sodium; sodium amide; metalalcoholates such as sodium methylate and sodium ethylate; organic basiccompounds such as pyridine, N-ethyldiisopropylamine,dimethylaminopyridine, triethylamine, tripropylamine, DBN, DBU and DABCOcan be exemplified. The reaction is carried out generally at roomtemperature to 250° C., preferably at room temperature to around 180°C., and the reaction is completed generally in about 1 to 24 hours. Intothe reaction system, alkali metal halide such as sodium iodide orpotassium iodide may be added.

Among cyclic amide derivatives represented by the general formula (1) ofthe present invention, those having acidic group can be formedcorresponding salts thereof by treating with pharmacologicallyacceptable basic compounds. As to the basic compounds, metal hydroxidessuch as sodium hydroxide, potassium hydroxide, lithium hydroxide andcalcium hydroxide; alkali metal carbonates or bicarbonates such assodium carbonate and sodium hydrogen carbonate; alkali metal alcoholatessuch as sodium methylate and potassium ethylate can be exemplified.Among cyclic amide derivatives represented by the general formula (1) ofthe present invention, those having basic group can be formedcorresponding salts thereof by treating with pharmacologicallyacceptable acids. As to the acids, inorganic acids such as sulfuricacid, nitric acid, hydrochloric acid and hydrobromic acid; organic acidssuch as acetic acid, p-toluenesulfonic acid, ethane-sulfonic acid,oxalic acid, maleic acid, citric acid, succinic acid and benzoic acidcan be exemplified.

The above-mentioned cyclic amide derivatives represented by the generalformula (1) involve inevitably their optical isomers.

The objective compounds obtained by various methods of each one of theseReaction formulae-1 to -9 are separated from the reaction system bymethods of usual separation means, and can be further purified. As tosuch separation and purification methods, distillation method,recrystallization method, column chromatography, ion exchangingchromatography, gel chromatography, affinity chromatography, preparativethin layer chromatography and solvent extraction method can beexemplified.

POSSIBILITY OF INDUSTRIAL UTILIZATION

Thus obtained cyclic amide derivatives of the present invention are usedas in the form of general preparations of pharmaceutical compositions.Said preparations are prepared by using common diluents or excipientsfor example fillers, bulking agents, binding agents, wetting agents,disintegrators, surface-active agents, lubricants and the like. Thesepreparations of pharmaceutical compositions can be selected from variousforms in accordance with the therapeutical purposes. As to the typicalforms thereof, tablets, pills, powders, liquors, suspensions, emulsions,granules, capsules, suppositories, injection preparations (solutions,suspensions), eye drops and eye ointments and the like. Furthermore,inhalants, spraying preparations such as external aerosol preparations,liquid coatings, lotions, gels, oily ointments, emulsion type ointmentssuch as O/W type hydrophilic ointments and W/O type water-absorbingointments, water-soluble ointments, creams, liniments, cataplasmas,dermatological pastes, plasters, emulsions for external use, and sheetform preparations can be exemplified.

For the purpose to shape in the form of tablets, carriers which arewidely known in this field can be used. For example, excipients such aslactose, white sugar, sodium chloride, glucose, urea, starch, calciumcarbonate, kaolin, crystalline cellulose and silicic acid; binderingagents such water, ethanol, propanol, simple syrup, glucose solution,starch solution, gelatin solution, carboxymethylcellulose, shelac,methyl cellulose, potassium phosphate and polyvinylpyrrolidon;disintegrating agents such as dried starch, sodium alginate, agar-agarpowder, lainalia powder, sodium hydrogen carbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate,mono-glyceride of stearate, starch and lactose; disintegrationinhibiting agents such as white sugar, stearin, coconut butter andhydrogenated oils; absorption accelerators such as quaternary ammoniumbases and sodium laurylsulfate; wetting agent such as glycerin andstarch; adsorption agents such as starch, lactose, kaolin, bentonite andcolloidal silicic acid; lubricants such as refined talc, stearates,boric acid powder, and polyethylene glycol, can be exemplified. In caseof preparing tablets, if necessary, they can be further coated withusual coating materials, for example make them into tablets coated withsugar, tablets coated with gelatin film, tablets coated with entericcoatings, tablets coated with films or double layer tablets as well asmultiple layer tablets.

For the purpose to shape in the form of pills, any carrier which isknown and used widely in this field can be used. For example, excipientssuch as glucose, lactose, starch, coconut butter, hydrogenated vegetableoils, kaolin and talc; binding agents such as powdered gum arabic,powdered tragacanth gum, gelatin and ethanol; disintegrating agents suchas laminalia and agar-agar are included can be used.

For the purpose to shape in the form of suppositories, carriers whichare known and widely used in this field can be used. For example,polyethylene glycols, coconut butter, higher alcohols, esters of higheralcohols, gelatin and semi-synthesized glycerides can be used.

Capsule preparations are prepared in accordance with conventionalmethod, by mixing the active ingredient compounds with theabove-exemplified various carriers, then the mixture is filled in hardgelatine capsules or soft capsules.

In the case of prepare injection preparations, solutions, emulsion andsuspensions are sterilized and are preferably make them isotonic to theblood. In making the preparations in the form of injections, the all ofdiluents which are widely used in this field can be used. For example,water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearylalcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitanfatty acid esters can be used. In this case, adequate amount of sodiumchloride, glucose or glycerin may be added to the desired injectionpreparations to make them isotonic to the blood, further usualdissolving agents, buffering agents and analgesic agents can be added.If necessary, coloring agents, preservative agents, perfumes, seasoningagents, sweetening agents and other medicines can also be added into thedesired injection preparations.

In case of prepare eye drops and eye ointments, the base materials aresuitably selected in accordance with desired form of the preparation,and thus preparations are sterilized. For example, in case of prepare aneye ointment, any type of conventional emulsion-ointment base,water-soluble ointment base and suspension-ointment base can be used. Asto typical example of these base materials, white petrolatam, refinedlanolin and liquid paraffin can be used. In case of prepare an eyedrops, as to the typical base material, sterilized distilled water canbe used.

The amount of cyclic amide derivative of the general formula (1) or saltthereof of the present invention to be contained in the preparation ofpharmaceutical composition is not specifically restricted, and it cansuitably be selected from a wide range, and generally it may becontained about 1 to 70% by weight in the whole composition.

Method for administering the pharmaceutical compositions of the presentinvention is not specifically restricted, and they can be applied invarious preparation forms, and is administered in accordance with age ofthe patient, distinction of the sex, other conditions and degree of thesymptoms. For example, tablets, pills, liquid preparations, suspensionpreparations, emulsion preparations, granular preparations and capsulepreparations are administered orally. In case of using injectionpreparations, they are administered intravenously singly or incombination with usual injection preparations such as glucose solutionsand amino acids solutions. If necessary, the injection preparations areadministered singly intramuscularly, intracutaneously, subcutaneously orintraperitoneally. The suppositories are administered into the rectum.In case of the preparation for external use, they are applied to theaffected parts.

In case of using the cyclic amide derivative of the present invention asin the form of cosmetics, it is added in skin creams, skin lotions orskin oils for sunburn protection and sunburn prevention. Furthermore, itis added into general cosmetics as for protecting ultraviolet rays andfor preventing ultra-violet rays, and also added as the activeingredient in agent for protecting sunburn and in agent for sunburnprevention.

Cosmetic preparations are concretely exemplified such as shampoo,body-shampoo, perfume, eau de cologne, nail enamel, enamel remover,dentifrice, rinse, face powder, eye liner, mascara, eye blow, hairgrooming preparation (hair conditioner, hair grower), common skin cream,milky lotion (for protection, cleansing and conditioning the skin),shaving cream, shaving lotion, eye cream, common toilet water (foremollient, cleansing and conditioning the skin), pack, cleansingpreparation, beauty oil, bath cosmetics, hair color, nail cream, mouthwashes, bleaching preparation, acne preparation, permanent wavepreparation, and hair remover.

As to the forms of these cosmetics, liquid preparation, oil preparation,lotion, liniment, oleaginous ointment base, emulsion type ointment basefor O/W type hydrophilic ointment and W/O type water-absorbing ointment,water-soluble ointment base, dermatological paste, plaster, adhesiveplaster, cream and milk lotion can be exemplified, and such forms maynot be restricted within these range. The cosmetics in the form of thesetypes can be prepared in accordance with conventional methods which areknown and widely used in this field.

For example, the ointment bases are used singly or in combination with 2or more of oily bases, and are used singly or in combination with 2 ormore of water-soluble ointment bases. As to these ointment bases areconcretely exemplified such as, peanut oil, sesame oil, soybean oil,sufflower oil, avocado oil, sunflower oil, corn oil, rapeseed oil,cottonseed oil, castor oil, camelliaseed oil, coconut oil, olive oil,poppy oil, cacao butter, beef tallow, hog fat lard, lanolin and thelike; chemically reformed products of these ointment bases byhydrogenation and the like; mineral oils such as petrolatum, paraffinoil and paraffin wax; silicone oil; squalane oil; higher fatty acidesters, higher fatty alcohols and waxes such as isopropyl myristate,n-butyl myristate, isopropyl linolate, propyl ricinolate, isopropylricinolate, isobutyl ricinolate, heptyl ricinolate, diethyl sebacate,diisopropyl adipate, cetyl alcohol, stearyl alcohol, bleached bees wax,spermaceti, Japan wax, lanolins, carnauba wax and shellac wax; higherfatty acids such as stearic acid, oleic acid and palmitic acid; mixturesof mono- di- and tri-glycerides of saturated or unsaturated fatty acidshaving 12 to 18 carbon atoms; polyhydric alcohols such as ethyleneglycol, polyethylene glycols, propylene glycol, polypropylene glycols,glycerin, batyl alcohol, pentaerythritol, sorbitol, and mannitol;vegetable gums such as gum arabic, gum benzoin, guaiac resin and gumtragacanth; natural water-soluble macromolecules such as gelatin,starch, casein, dextrin, pectin, pectin sodium, sodium alginate, methylcellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, nitrocellulose and crystallinecellulose; synthetic water-soluble macro-molecules such as polyvinylalcohols, polyvinylmethyl ethers, polyvinylpyrrolidones, sodiumpolyacrylates, carboxyvinyl polymers and polyethyleneimines; surfaceactive agents such as nonionic surfactants, cathionic surfactants,amphoteric surfactants and anionic surfactants; ethanol, isopropanol andwater.

In case of preparing the above-mentioned cosmetic products, varioustypes of cosmetic base materials known in the art, for exampleexcipients, binding agents, lubricants and disintegrating agents can beused in accordance with the necessity. Further, if necessary, varioustypes of oils and fats, waxes, hydrocarbons, fatty acids, higheralcohols; oily materials such as ester oils and metallic soaps; liquidextracts of animals and vagetables; medicinal agents such as vitamins,hormons and amino acids; surface active agents, colors, dyestuffs,pigments, perfumes, preservatives, germicides, wetting agent, thickeningagents, antioxidants and metal chelating agents; as well as varioustypes of ingredients and additives which are known in the art can beused by combining thereof. In addition to the above, these cosmeticpreparations thus obtained can also be used by diluting with suitablesolvent such as water or olive oil.

The amount of cyclic amide derivative represented by the general formula(1) or salt thereof of the present invention to be contained as theactive ingredient in the cosmetic preparations is not specificallyrestricted and it can be selected suitably from a wide range, andgenerally the cyclic amide derivative or salt thereof may be containedabout 0.1 to 50% by weight.

Administration dose of the cyclic amide derivative represented by thegeneral formula (1) or salt thereof being contained as the activeingredient in the preparation of pharmaceutical composition or thecosmetic preparation of the present invention may be selected inaccordance with method of administration, age of the patient,distinction of the sex and other conditions, degree of disease and soforth. Generally in case of using as for pharmaceutical composition,about 0.6 to 50 mg/kg of the body weight/day of the active ingredientmay be administered, and in case of using as for cosmetic preparation,about 0.1 to 30 mg/kg of the body weight/day of the active ingredientmay be administered. These preparations may be administered divisionallyin 2 to 4 times a day.

EXAMPLES

The present invention will be explained in detail by showing Referenceexamples, Examples and Pharmacological test results as follows.

Reference Example 1

32.6 Grams of 3,4-dihydro-6-hydroxy-2(1H)-quinolinone was dissolved in500 ml of methanol containing 12.6 g of potassium hydroxide. Understirring this solution, 20 ml of allyl bromide was added thereto at roomtemperature. The reaction mixture was stirred at room temperature for 1hour, and further stirred at 60° C. for 4 hours. After the reaction, thereaction mixture was concentrated to a half volume under reducedpressure, then 500 ml of water was added and stirred vigorously, thecrystals precipitated were collected by filtration. The crystals werewashed with water and small amount of diethyl ether in this order, anddried. Recrystallized from ethanol, 28 g (68.9%) of6-allyloxy-3,4-dihydro-2(1H)-quinolinone was obtained. Colorlessneedle-like crystals (recrystallized from ethanol)

Melting point: 123°-125° C.

By using suitable starting materials, and employing the reactioncondition as well as after treatment procedures similar to those carriedout in Reference example 1, there were prepared compounds of ReferenceExamples 2 to 6 as follows.

Reference Example 2

7-Allyloxy-3,4-dihydro-2(1H)-quinolinone

Colorless needle-like crystals (recrystallized from ethanol)

Melting point: 98°-101°.

Reference Example 3

6-Allyloxy-2(1H)-quinolinone

Colorless needle-like crystals (recrystallized from methanol)

Melting point: 193°-194°.

Reference Example 4

7-Allyloxy-2(1H)-quinolinone

Colorless needle-like crystals (recrystallized from methanol)

Melting point: 151°-153° C.

Reference Example 5

7-Allyloxy-3(2H)-1,4-benzoxazinone

¹ H-NMR (CDCl₃, TMS, ppm):

4.49-4.53 (2H, m), 4.59 (2H, s), 5.25-5.45 (2H, m), 5.95-6.10(1H, m),6.50-6.59 (2H, m), 6.72 (1H, d), 8.51 (1H, s).

Reference Example 6

6-Allyloxy-3(2H)-1,4-benzoxazinone

¹ H-NMR (CDCl₃, TMS, ppm):

4.48-4.52 (2H, m), 4.57 (2H, s), 5.25-5.46 (2H, m), 5.92-6.10 (1H, m),6.42 (1H, d), 6.45 (1H, d--d), 6.88 (1H, d), 8.76 (1H, s).

Reference Example 7

10.2 Grams of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in100 ml of dimethyl-formamide (DMF), then at room temperature, 2.2 g of60% oily sodium hydride was added little by little thereto, and thereaction mixture was stirred at 25° to 40° C. until generation ofhydrogen was stopped. The reaction mixture was cooled to roomtemperature, 9.1 g of prenyl bromide was added thereto and stirred atroom temperature for 8 hours. After the reaction was completed, waterwas added, and the reaction mixture was extracted with methylenechloride. The methylene chloride extract was washed with water and anaqueous solution saturated with sodium chloride in this order, then thuswashed extract was dried with anhydrous magnesium sulfate. Magnesiumsulfate was removed by filtration and concentrated. Thus obtained oilyresidue was subjected to refining and separating by means of a silicagel flush column chromatography by using mixed solvent of ethylacetate:n-hexane (1:10 to 1:2) as an eluent to obtain 10.2 g (59.7%) of6-allyloxy-3,4-dihydro-1-prenyl-2-(1H)-quinolinone.

Light yellow oily substance:

¹ H-NMR (CDCl₃, ppm):

1.74 (3H, s), 1.82 (3H, s), 2.61-2.69 (2H, m), 2.88-2.92 (2H, m),4.52-4.56 (2H, m), 5.11-5.17 (1H, m), 5.28-5.49 (2H, m), 5.98-6.15 (2H,m), 8.77-8.92 (3H, m).

Reference Example 8

10.2 Grams of 6-allyloxy-2(1H)-quinolinone was dissolved in 100 ml ofdimethylformamide, then 2.2 g of 60% oily sodium hydride and 9.1 g ofprenyl bromide were added thereto by the procedures similar to thoseemployed in Reference example 7 and reacted. Then, thus obtainedreaction mixture was treated and oily mixture was obtained. This mixturewas subjected to separation and refining by means of a silica gel flushcolumn chromatography in which a mixture of ethyl acetate:n-hexane (1:10to 1:2) was used as an eluent. Colorless to light yellow oily product,which was obtained by concentrating the second eluate portion underreduced pressure, was allowed to stand at room temperature, then it wascrystallized. There was obtained 4.7 g (34.9%) of6-allyloxy-2-prenyloxy-quinoline by recrystallization from n-hexane.Colorless needle-like crystals (recrystallized from n-hexane)

Melting point: 53°-54° C.

Reference Example 9

The third eluate portion of silica gel flush column chromatography ofReference example 8 was collected, and concentrated under reducedpressure. Thus obtained oily product was allowed to stand at roomtemperature, then it was crystallized to obtain 5.7 g (43.4%) of6-allyloxy-1-prenyl-2(1H)-quinolinone. Colorless granular crystals(recrystallized from n-hexane)

Melting point: 80°-82° C.

Reference Example 10

2 Grams of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 50ml of dimethyl-formamide, then 0.5 g of 60% oily sodium hydride and 5 mlof p-bromoanisole were added thereto by the procedures similar to thoseemployed in Reference example 7, further 4 g of cuprous chloride wasadded, and stirred at 120° C. for 24 hours. The inorganic materials wereremoved by filtration, and the filtrate was concentrated under reducedpressure. Thus obtained residual product was subjected to extractionwith 200 ml of methylene chloride, the extract was washed with water andan aqueous solution saturated with sodium chloride. Then the extract wasconcentrated and subjected to purification by passing through a silicagel column, there was obtained 1.3 g (42%) of6-allyloxy-3,4-dihydro-1-(4-methoxyphenyl)-2(1H)-quinolinone.

Light yellow oily product.

¹ H-NMR (CDCl₃, ppm):

2.79-2.69 (2H, t), 3.01 (2H, t), 3.85 (3H, s), 4.49-4.56 (2H, m),5.24-5.44 (2H, m), 5.95-6.11 (1H, m), 6.30 (1H, d), 6.59 (1H, m), 6.78(1H, d),7.00 (2H, d),

7.14 (2H, d).

By the procedure similar to that of employed in Reference example 7,there were obtained compounds of Reference examples 11-13; by theprocedures similar to those of employed in Reference examples 8 and 9,there were obtained compounds of Reference examples 14 to 17; and by theprocedure similar to those of employed in Reference example 10, therewere obtained compounds of Reference examples 18 to 20, respectively asfollows.

Reference Example 11

7-Allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone.

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

1.72 (3H, s), 1.80 (3H, s), 2.60-2.64 (2H, m), 2.80-2.86 (2H, m),4.51-4.54 (4H, m), 5.10-5.13 (1H, m), 5.27-5.45 (2H, m), 5.98-6.11 (1H,m), 6.52-6.59 (2H, m), 7.04 (1H, d).

Reference Example 12

6-Allyloxy-1-cinnamyl-3,4-dihydro-2(1H)-quinolinone

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

2.68-2.73 (2H, m), 2.88-2.94 (2H, m), 4.49-4.53 (2H, m), 4.69-4.71 (2H,m), 5.27-5.45 (2H, m), 5.99-6.08 (1H, m), 6.22-6.31 (1H, m), 6.53 (1H,d), 6.74-6.77 (2H, m), 7.00 (1H, m), 7.21-7.37 (5H, m).

Reference Example 13

6-Allyloxy-1-(4-allyloxy-3-methoxybenzyl)-3, 4-dihydro-2(1H)-quinolinone

Colorless needle-like crystals (recrystallized from diethylether-n-hexane), Melting point: 93°-65° C.

Reference Example 14

1-Allyl-6-allyloxy-2(1H)-quinolinone

Colorless granular crystals (recrystallized from petroleum ether),Melting point: 49°-51° C.

Reference Example 15

2,6-Diallyloxyquinoline

Colorless granular crystals (recrystallized from n-hexane)

Melting point: 58°-60° C.

Reference Example 16

7-Allyloxy-1-prenyl-2(1H)-quinolinone

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

1.72 (3H, s), 1.89 (3H, s), 4.60-4.63 (2H, m), 4.89 (2H, d), 5.11-5.15(1H, m), 5.31-5.48 (2H, m), 6.02-6.13 (1H, m), 6.55 (1H, d), 6.79-6.84(3H, m), 7.44 (1H, d), 7.58 (1H, d).

Reference Example 17

7-Allyloxy-2-prenyloxyquinoline

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

1.82 (6H, s), 4.66-4.70 (2H, m), 4.99-5.01 (2H, m), 5.31-5.62 (3H, m),6.76 (1H, d), 6.99-7.03 (3H, m), 7.21 (1H, d), 7.59 (1H, d), 7.92 (1H,d).

Reference Example 18

5-Allylyoxy-3,4-dihydro-1-phenyl-2(1H)-quinolinone

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

2.79 (2H, t), 3.11 (2H, t), 4.55-4.59 (2H, m), 5.25-5.50 (2H, m), 5.98(1H, d), 6.00-6.20 (1H, m), 6.58 (1H, d), 7.21 (1H, t), 7.24-7.55 (5H,m).

Reference Example 19

6-Allyloxy-3,4-dihydro-1-(4-fluorophenyl)-2(1H)-quinolinone

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

2.79 (2H, t), 3.01 (2H, t), 4.49-4.56 (2H, m), 5.25-5.45 (2H, m),5.95-6.11 (1H, m), 6.26 (1H, d), 5.68-6.62 (1H, m), 6.79 (1H, d),7.13-7.14 (4H, m).

Reference Example 20

6-Allyloxy-3,4-dihydro-1-(3,4-dimethoxy-phenyl)-2(1H)-quinolinone

Light yellow oily product

¹ H-NMR (CDCl₃, ppm):

2.80 (2H, t), 3.03 (2H, t), 3.85 (3H, s), 3.93 (3H, s), 4.49-4.56 (2H,m), 5.24-5.45 (2H, m), 5.95-6.11 (1H, m), 6.33 (1H, d), 6.58-6.62 (1H,m), 6.71 (1H, d), 6.78-6.83 (2H, m), 6.97 (2H, d)

In place of the starting material of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone used in Reference example 7, each of thestarting materials of Reference examples 5 and 6 or5-hydroxybenzoxazolinone was used, and by the procedure used inReference example 7, there were prepared compounds of Reference examples21-23 as follows.

Reference Example 21

4-Allyl-7-allyloxy-3(2H)-1,4-benzoxazinone

Yellow oily product

¹ H-NMR (CDCl₃, ppm):

4.45-4.55 (4H, m), 4.62 (2H, s), 5.25-5.45 (4H, m), 5.75-6.10 (2H, m),6.50-6.60 (2H, m), 6.87 (1H, d).

Reference Example 22

4-Allyl-6-allyloxy-3(2H)-1,4-benzoxazinone

Yellow oily product

¹ H-NMR (CDCl₃, ppm):

4.45-4.54 (4H, m), 4.59 (2H, s), 5.15-5.45 (4H, m), 5.80-6.15 (2H, m),6.53 (1H, d), 6.60 (1H, d), 6.90 (1H, d).

Reference Example 23

3-Allyl-5-allyloxybenzoxazolinone

Yellow oily product

¹ H-NMR (CDCl₃, ppm):

4.40-4.45 (2H, m), 4.50-4.55 (2H, m), 5.25-5.45 (4H, m), 5.80-6.15 (2H,m), 6.58 (1H, d), 6.63 (1H,. m), 7.08 (1H, d).

Example 1

10 Grams of 6-allyloxy-2(1H)-quinolinone was suspended in 50 ml oftetralin, and this suspension was stirred at 200° to 230° C. for 4 hoursin nitrogen gas atmosphere. After the reaction, the reaction mixture wascooled to room temperature. The crystals thus precipitated werecollected by filtration, washed with n-hexane and a small amount ofdiethyl ether in this order and dried. There was obtained 10 g (100%) of5-allyl-6-hydroxy-2(1H)-quinolinone as crystalline powder. Meltingpoint: Decomposed from 290° C.

¹ H-NMR (DMSO-d₆, ppm):

3.60 (2H, d), 4.88-4.97 (2H, m), 5.82-5.98 (1H, m), 6.45 (2H, d), 7.07(2H, s), 7.92 (1H, d), 9.32 (1H, s), 12.50 (1H, s).

Example 2

4 Grams of 2,6-diallyloxyquinoline was reacted similarly as in Example1, and the reaction mixture thus obtained was treated, there wasobtained 4 g (100%) of 5-allyl-6-hydroxy-2(1H)-quinolinone as powderycrystals.

Example 3

2 Grams of 6-allyloxy-1-prenyl-2(1H)-quinolinone was reacted similarlyas in Example 1, and the reaction mixture thus obtained was treated,there was obtained 2 g (100%) of5-allyl-6-hydroxy-l-prenyl-2(1H)-quinolinone.

Pale yellow needle-like crystals (recrystallized fromchloroform-methanol). Melting point: 224°-228° C.

Example 4

7.8 Grams of 7-allyloxy-1-prenyl-2(1H)-quinolinone was reacted similarlyas in Example 1, and the reaction mixture thus obtained was treated, anddissolved in a small amount of chloroform, then the chloroform solutionwas subjected to purification by means of a silica gel flush columnchromatography. The firstly eluted portion, which was eluted withmethylene chloride-methanol (100:1-50:1) i.e., the 1st eluate portion:3.8 g (14.1%) of 8-allyl-7-hydroxy-3-prenyl-2(1H)-quinolinone, paleyellow needle-like crystals, melting point: 138°-142° C.! was removed,then the secondary eluted portion (the 2nd eluate portion) wascollected, concentrated and dried, there was obtained 0.8 g (10.3%) of8-allyl-7-hydroxy-1-prenyl-2(1H)-quinolinone.

Pale yellow powdery crystals (recrystallized from ethyl acetate).Melting point: 198°-203° C.

Example 5

From the flush column chromatography in Example 4, the finally elutedportion was collected, concentrated and dried, there was obtained 4 g(14.9%) of 8-allyl-7-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from methanol).

Melting point: 207°-209° C.

Example 6

4 Grams of 1-allyl-6-allyoxy-2(1H)-quinolinone was reacted similarly asin Example 1 and treated, there was obtained 4 g (100%) of1,5-diallyl-6-hydroxy-2(1H)-quinolinone. Colorless granular crystals(recrystallized from methanol). Melting point: 205°-206° C.

Example 7

20.3 Grams of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was reactedsimilarly as in Example 1 and treated, there was obtained 20 g (100%) of1:1 mixture of 5-allyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and7-allyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. To this mixture wasadded 1 liter of acetone and boiled for 1 hour, the insoluble matter wascollected by filtration, washed with acetone and dried, there wasobtained 6.7 g (33%) of 5-allyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White crystalline powder. Melting point: 236°-239° C.

Example 8

From 20.3 g of 7-allyloxy-3,4-dihydro-2(1H)-quinolinone which wasreacted similarly as in Example 1 and treated, there was obtained 18 g(88.7%) of mixture of 6-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinoneand 8-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

Example 9

5 Grams of 6-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone was reactedsimilarly as in Example 1 and treated, thus obtained mixture wassubjected to purification by means of a flush column chromatography byusing ethyl acetate-n-hexane (1:100 to 1:25). The firstly eluted portionwas collected and concentrated under reduced pressure. The residue thusobtained was recrystallized from ethyl acetate-n-hexane, there wasobtained 0.8 g (16%) of5-allyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from ethyl acetate).Melting point: 182°-184° C.

Example 10

From the silica gel flush column chromatography in Example 9, the secondeluted portion was collected, and the solvent was removed bydistillation, there was obtained 1.8 g (36%) of7-allyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone.

Colorless plate crystals (recrystallized from ethyl acetate). Meltingpoint: 148°-150° C.

Corresponding starting materials are reacted similarly as in Examples9-10, and the reaction mixture thus obtained were subjected toseparation and purification by means of silica gel columnchromatography, there were obtained compounds of Examples 11 and 12 asfollows.

Example 11

6-Allyl-3,4-dihydro-7-hydroxy-1-prenyl-2(1H)-quinolinone

Colorless needle-like crystals (recrystallized from water-containingethanol). Melting point: 113°-114° C.

Example 12

8-Allyl-3,4-dihydro-7-hydroxy-1-prenyl-2(1H)-quinolinone.

Colorless granular crystals (recrystallized from diethyl ether). Meltingpoint 143°-145° C.

Example 13

16 Grams of 6-allyloxy-1-cinnamyl-3,4-dihydro-2(1H)-quinolinone obtainedin Reference example 12 was reacted similarly as in Example 1, and thusobtained reaction mixture was treated similarly, there was obtained 10.6g (66.6%) of mixture of7-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and5-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. Said mixturewas subjected to purification by means of a flush column chromatography.The thirdly eluted portion was collected, and concentrated under reducedpressure, there was obtained7-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone. Colorlessgranular crystals (recrystallized from ethanol). Melting point:199°-203° C.

Example 14

6.1 Grams of the mixture of6-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone and8-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone obtained in Example 8was dissolved in 200 ml of methanol containing 1.8 g of potassiumhydroxide. Under stirring, 3 ml of allyl bromide was added thereto atroom temperature. The reaction mixture was stirred at room temperaturefor 4 hours, and further stirred at 60° C. for 1 hour. After thereaction was finished, the reaction mixture was concentrated underreduced pressure, next 200 ml of water was added and stirred vigorously,then extracted with 500 ml of ethyl acetate. The extract was washed withwater and an aqueous solution saturated with sodium chloride, and driedwith anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, and the filtrate was concentrated to dryness. This mixturewas subjected to purification by means of a flush column chromatographyby using methylene chloride-methanol (100:1). The first eluted portionwas collected and concentrated under reduced pressure, there wasobtained 4.4 g (60%) of8-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless needle-likecrystals (recrystallized from ethyl acetate-n-hexane). Melting point:119°-121° C.

Example 15

From the flush column chromatography in Example 14, the secondary elutedportion was collected, concentrated and dried, there was obtained 2.8 g(38%) of 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone was obtained.

Colorless needle-like crystals (recrystallized from ethylacetate-n-hexane). Melting point: 137°-139° C. Example 16

20.3 Grams of the mixture of5-allyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and7-allyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained in Example 7was dissolved in 500 ml of methanol containing 12.6 g of potassiumhydroxide. Under stirring, 20 ml of allyl bromide was added thereto atroom temperature. The reaction mixture was stirred at room temperaturefor 1 hour, and further stirred at 60° C. for 4 hours. After thereaction was finished, the reaction mixture was concentrated underreduced pressure to a half volume, 500 ml of water was added thereto andstirred vigorously, then extracted with 500 ml of ethyl acetate. Theethyl acetate extract was washed with water and an aqueous solutionsaturated with sodium chloride, and dried with anhydrous magnesiumsulfate. The magnesium sulfate was removed by filtration, and thefiltrate was concentrated and dried. Recrystallized from ethylacetate-n-hexane, there was obtained 18 g of the mixture of5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone. This mixture was usedas the starting material in the next Example 17 without subjected toseparating the two ingredients.

Example 17

10.2 Grams of the mixture of5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16was dissolved in 100 ml of dimethylformamide, then 2.2 g of 60% oilysodium hydride was added little by little, and stirred at 25° to 40° C.until generation of hydrogen gas was ceased. After the reaction mixturewas cooled to room temperature, 9.1 g of prenyl bromide was added andstirred at room temperature for 8 hours. After the reaction wasfinished, water was added and extracted with methylene chloride, thenthe extract was washed with water and an aqueous solution saturated withsodium chloride in this order, and dried with anhydrous magnesiumsulfate. The magnesium sulfate was removed by filtration and thefiltrate was concentrated. Thus obtained residual oily product wassubjected to separation and purification by means of a silica gel flushcolumn chromatography, there was obtained 10.2 g (59.7%) of7-allyl-6-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone.

Colorless granular crystals (recrystallized from ethanol).

Melting point: 86°-88° C.

The mixture of 5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16was used as the starting materials, and reacted with cinnamyl bromide orcyclohexyl methyl chloride similarly as in Example 17, and thus obtainedreaction mixture was treated similarly as in Example 17, then subjectedto separation and purification by means of a silica gel columnchromatography, there were obtained compounds of Examples 18 and 19 asfollows.

Example 18

7-Allyl-6-allyloxy-1-cinnamyl-3,4-dihydro-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from n-hexane).

Melting point: 76°-77° C.

Example 19

7-Allyl-6-allyloxy-1-cyclohexylmethyl-3,4-dihydro-2(1H)-quinolinone.

Yellow oily product.

¹ H-NMR (CDCl₃, ppm):

0.96-1.20 (5H, m), 1.60-1.75 (6H, m), 2.59-2.63 (2H, m), 2.84 (2H, t),3.41 (2H, d), 3.81 (2H, d), 4.51-4.54 (2H, m), 5.05-5.12 (2H, m),5.25-5.47 (2H, m), 5.93-6.12 (1H, m), 6.66 (1H, s), 6.80 (1H, s)

Example 20

81 Grams of 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained inExample 15 was dissolved in 500 ml of dimethylformamide, then 13 g of60% oily sodium hydride and 50 g of prenyl bromide were added theretoand reacted similarly as in Example 17, after the reaction was finished,the reaction mixture was treated similarly, there was obtained yellowoily product. This oily product was subjected to treatment by means of asilica gel flush column chromatography by using a mixed solvent ofmethylene chloride-methanol (100:1) as the eluent. The secondary elutedportion was collected and concentrated, there was obtained 67 g (64.6%)of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone as paleyellow oily product. This oily product become a solid matter then it wasallowed to stand at below 20° C., the solid matter was washed withice-cooled petroleum ether to change white solid, dried in a desiccatorand pulverized, there was isolated white powdery product.

Pale yellow oily or white solid. Melting point: 20-28° C.

¹ H-NMR (CDCl₃, ppm):

1.73 (3H, s), 1.81 (3H, s), 2.58-2.66 (2H, m), 2.76-2.84 (2H, m),4.48-4.53 (2H, m), 5.02-5.14 (3H, m), 5.25-5.45 (2H, m), 5.91-6.10 (2H,m), 6.52 (1H, s), 6.90 (1H, s).

Example 21

3.19 Grams of the mixture of5-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and7-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained inExample 13 was dissolved in 100 ml of methanol containing 1 g ofpotassium hydroxide. Under stirring, 2 g of cinnamy bromide was addedthereto at room temperature, then stirred at room temperature for 1hour, further stirred at 60° C. for 4 hours. After the reaction wasfinished, the reaction mixture was concentrated to a half volume underreduced pressure, 100 ml of water was added and stirred vigorously, thenextracted with 200 ml of ethyl acetate. The extract was washed withwater and an aqueous solution saturated with sodium chloride and driedwith anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, the filtrate was concentrated to dryness. The residue wassubjected to treatment by means of a silica gel flush columnchromatography by using a mixed solvent of ethyl acetate: n-hexane asthe eluent. The second eluted portion was collected and concentrated andcrystallized from diethyl ether-n-hexane, there was obtained 1.8 g(41.4%) of5-allyl-1-cinnamyl-6-cinnamyloxy-3,4-dihydro-2(1H)-quinolinone.Colorless granular crystals (recrystallized from diethylether-n-hexane). Melting point: 66°-68° C.

Example 22

From the flush column chromatography in Example 21, the later elutedportions were collected, concentrated and crystallized, there wasobtained 2.0 g (45.9%) of7-allyl-1-cinnamyl-6-cinnamyloxy-3,4-dihydro-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from diethylether-n-hexane). Melting point: 88°-89° C.

By using 1-bromo-2-cyclohexene and treated similarly as in Examples 21and 22, the compounds of Examples 23 and 24 were prepared.

Example 23

5-Allyl-1-cinnamyl-6-(2-cyclohexenyl)oxy-3,4-dihydro-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from diethylether-n-hexane). Melting point: 103°-104° C.

Example 24

7-Allyl-1-cinnamyl-6-(2-cyclohexenyl)oxy-3,4-dihydro-2(1H)-quinolinone.

Yellow oily product

¹ H-NMR (CDCl₃, ppm):

1.55-2.20 (6H, m), 2.64 (2H, t), 2.89 (2H, t), 3.35 (2H, d), 4.69 (3H,d), 5.01-5.09 (2H, m), 5.83-5.97 (3H, m), 6.18-6.27 (1H, m), 6.56 (1H,d), 6.73 (1H, s), 6.73 (1H, s), 6.90 (1H, s), 7.01-7.35 (5H, m).

Example 25

2.43 Grams of the mixture obtained in Example 8 was dissolved in 20 mlof tetralin, and reacted similarly as in Example 1. After the reactionwas finished, the reaction mixture was cooled to room temperature, andwas subjected to purification by passing through a silica gel column,there was obtained 1.8 g (74%) of6,8-diallyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone.

Cololess needle-like crystals (recrystallized from diethylether-n-hexane). Melting point: 86°-88° C.

Example 26

12.2 Grams of the mixture obtained in Example 16 was dissolved in 100 mlof tetralin, and reacted similarly as in Example 1. After the reactionwas finished, the reaction mixture was cooled to room temperature, andwas subjected to purification by passing through a silica gel column,there was obtained 8.7 g (71%) of5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

Cololess needle-like crystals (recrystallized from methylenechloride-n-hexane). Melting point: 118°-119° C.

Example 27

2 Grams of 7-allyl-6-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinoneobtained in Example 20 was dissolved in 20 ml of tetralin, and reactedsimilarly as in Example 1. After the reaction was finished, the reactionmixture was cooled to room temperature, and was subjected topurification by passing through a silica gel column, there was obtained1 g (50%) of5,7-diallyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone.

Colorless flake crystals (recrystallized from ethyl acetate-n-hexane).Melting point: 133°-135° C.

Example 28

10 Grams of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinoneobtained in Example 20 was dissolved in 50 ml of tetralin and stirred at200° to 230° C. for 3 hours. After cooling, the reaction mixture wassubjected to purification by passing through a silica gel column, therewas obtained 7.8 g (78%) of6,8-diallyl-3,4-dihydro-7-hydroxy-1-prenyl-2(1H)-quinolinone.

Colorless flake crystals (recrystallized from ethyl acetate-n-hexane).Melting point 94°-96° C.

Example 29

2.4 Grams of the mixture of6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone and6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone as the reactionintermediate obtained in Example 14 was dissolved in 20 ml ofdimethylformamide, then 0.6 g of 60% oily sodium hydride and 2.5 g ofcinnamyl bromide were added thereto at room temperature and reactedsimilarly as in Reference example 7, there was obtained yellow oilyproduct by treating thus obtained reaction mixture. Said oily productwas dissolved in 50 ml of tetralin and stirred at 200° to 230° C. for 3hours. After cooling, the reaction mixture was subjected to purificationby passing through a silica gel column, there was obtained 1.2 g (33.4%)of 6,8-diallyl-1-cinnamyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone. Paleyellow flake crystals (recrystallized from isopropyl ether). Meltingpoint: 132°-138° C.

Example 30

1.34 Grams of 5-allyl-6-hydroxy-1-prenyl-2(1H)-quinolinone obtained asshown in Example 3 was dissolved in 100 ml of dimethylformamide, then0.5 g of potassium carbonate and 1 ml of allyl bromide were addedthereto and stirred at room temperature over-night. After thedimethylformamide was removed by distillation under reduced pressure,the reaction mixture was extracted with methylene chloride. The extractwas washed with water, dried with anhydrous magnesium sulfate, thensolvent was removed by distillation under reduced pressure, thusobtained residue was dissolved in 10 ml of tetralin and stirred at 200°to 230° C. for 6 hours. After cooling, the reaction mixture wassubjected to purification by passing through a silica gel column, therewas obtained 0.5 g (34.3%) of5,7-diallyl-6-hydroxy-1-prenyl-2(1H)-quinolinone.

Yellow needle-like crystals (recrystallized from acetone). Meltingpoint: 187°-189° C.

Example 31

5-Allyloxy-3,4-dihydro-1-phenyl-2(1H)-quinolinone was treated similarlyas in Example 1, there was obtained6-allyl-3,4-dihydro-5-hydroxy-1-phenyl-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from ethylacetate-n-hexane). Melting point: 177°-178.5° C.

Example 32

1.2 Grams of6-allyloxy-3,4-dihydro-1-(4-methoxyphenyl)-2(1H)-quinolinone wasdissolved in 10 ml of tetralin and reacted similarly as in Example 1,the reaction mixture was treated, there was obtained 0.9 g of mixture of5-allyl-3,4-dihydro-6-hydroxy-1-(4-methoxyphenyl)-2(1H)-quinolinone and7-allyl-3,4-dihydro-6-hydroxy-1-(4-methoxyphenyl)-2(1H)-quinolinone. 0.9Grams of this mixture was dissolved in 20 ml of dimethylformamide, then1 g of potassium carbonate and 1 ml of allyl bromide were added theretoand stirred at room temperature overnight. The reaction mixture wasextracted with 100 ml of ethyl acetate, the extract was washed withwater and dried with anhydrous magnesium sulfate. After removal of theethyl acetate by distillation under reduced pressure, 10 ml of tetralinwas added and the whole mixture was stirred at 200° C. for 6 hours.After cooling, the reaction mixture was subjected to purification bypassing through a silica gel column, there was obtained 0.5 g (37%) of5,7-diallyl-3,4-dihydro-6-hydroxy-1-(4-methoxyphenyl)-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from n-hexane). Meltingpoint: 153.5°-154.5° C.

Example 33

4.8 Grams of the mixture obtained in Example 16 was dissolved in 100 mlof dimethylformamide, to this solution, 4 g of10-tetrahydropyranyloxy-1-bromodecane, (which was prepared by reactingat room temperature 2.2 g of 60% oily sodium hydride, 10-bromodecanoland dihydropyran in the presence of a small amount of concentratedhydrochloric acid) was added and reacted similarly as in Referenceexample 7, thus obtained reaction mixture was treated to obtain 4.2 g ofmixture of5-allyl-6-allyloxy-3,4-dihydro-1-(10-tetrahydropyranyloxy)decyl-2(1H)-quinolinoneand7-allyl-6-allyloxy-3,4-dihydro-1-(10-tetrahydropyranyloxy)decyl-2(1H)-quinolinoneas in the form of oily product. Without being isolated and purified,this mixture was dissolved in 20 ml of decalin, and was subjected toClaisen rearrangement similarly as in Example 29. After cooling, to thisreaction mixture was added 1 ml of hydrochloric acid and 100 ml ofwater-containing ethanol, then stirred at room temperature for 12 hours.The ethanol was removed by distillation under reduced pressure, thusobtained residue was subjected to isolation and purification by means ofa silica gel flush column chromatography by using a mixed solvent ofethyl acetate:n-hexane (1:10 to 1:2) as the eluent, there was obtained1.7 g (32.2%) of5,7-diallyl-3,4-dihydro-6-hydroxy-1-(10-hydroxy)-decyl-2(1H)-quinolinone.

Pale yellow oily product.

¹ H-NMR (CDCl₃, ppm):

1.29 (12H, br), 1.45-1.66 (5H, m), 2.52-2.58 (2H, m), 2.76-2.82 (2H, m),3.43 (4H, t), 3.60-3.67 (2H, m), 3.88 (2H, t), 4.93-5.23 (5H, m),5.89-6.06 (2H, m), 6.68 (1H, s).

Example 34

1.5 Grams of 7-allyloxy-3(2H)-1,4-benzoxazinone obtained in Referenceexample 5 was dissolved in 10 ml of tetralin then reacted and treatedsimilarly as in Example 1, there is obtained 1.1 g of mixture of6-allyl-7-hydroxy-2(1H)-benzoxazinone and8-allyl-7-hydroxy-2(1H)-benzoxazinone. 1.1 Grams of this mixture wasdissolved in 20 ml of dimethylformamide, then 1 g of potassium carbonateand 1 ml of allyl bromide were added thereto and stirred at roomtemperature overnight. The reaction mixture was extracted with 100 ml ofethyl acetate, after washed with water, the extract was dried withanhydrous magnesium sulfate. After removal of the ethyl acetate bydistillation under reduced pressure, 20 ml of tetralin was added andstirred at 180° C. for 6 hours. After cooling, the reaction mixture wassubjected to purification by passing through a silica gel column, therewas obtained 0.2 g (11%) of 6,8-diallyl-7-hydroxy-3(2H) -1,4-benzoxazinone.

Pale brown powdery crystals (recrystallized fromisopropylether-n-hexane). Melting point: 94°-95° C.

Example 35

1.5 Grams of 6-allyloxy-3(2H)-1,4-benzoxazinone obtained in Referenceexample 6, was reacted and treated similarly as in Example 34, there wasobtained 0.4 g (22%) of 5,7-diallyl-6-hydroxy-3-(2H)-1,4-benzoxazinone.

White powdery crystals (recrystallized from ethyl acetate-n-hexane).Melting point: 114°-115° C.

Example 36

0.8 Gram of 4-allyl-7-allyloxy-3(2H)-1,4-benzoxazinone obtained inReference example 21, was reacted and treated similarly as in Example34, there was obtained 0.4 g (35%) of7-hydroxy-4,6,8-triallyl-3(2H)-1,4-benzoxazinone.

White powdery crystals (recrystallized from isopropyl ether). Meltingpoint: 91°-92° C.

Example 37

1.9 Grams of 4-allyl-6-allyloxy-3(2H)-1,4-benzoxazinone obtained inReference example 22, was reacted and treated similarly as in Example34, there was obtained 0.9 g (18%) of6-hydroxy-4,5,7-triallyl-3(2H)-1,4-benzoxazinone.

White powdery crystals (recrystallized from isopropyl ether-n-hexane).Melting point: 71°-73° C.

Example 38

1.9 Grams of 3-allyl-5-allyloxybenzoxazolinone obtained in Referenceexample 23 was dissolved in 10 ml of tetralin, and reacted and treatedsimilarly as in Example 34, there was obtained 1.5 g (61%) of5-hydroxy-3,4,6-triallylbenzoxazolinone.

Brown oily product

¹ H-NMR (CDCl₃, ppm):

3.42 (2H, d), 3.54 (2H, d), 4.48-4.54 (2H, m), 4.94-5.30 (6H, m), 5.05(1H, s), 5.89-6.11 (3H, m), 6.92 (1H, s).

Example 39

3.34 Grams of 6-hydroxybenzothiazolinone was dissolved in 50 ml ofdimethylformamide, then 3.5 g of potassium carbonate was added theretoand stirred at 70° C. for 30 minutes. After cooling, to the reactionmixture was added 3 ml of allyl bromide and stirred for 5 hours, thenthe dimethylformamide was removed by distillation under reducedpressure. To thus obtained residue was added water and extracted withchloroform, the extract was washed with water, dried and concentrated toobtain an oily product. This oily product was used as the startingmaterial, was reacted and treated similarly as in Example 34, there wasobtained 0.4 g (23%) of 6-hydroxy-3,5,7-triallylbenzothiazolinone.

Colorless flake crystals (recrystallized from methylenechloride-n-hexane). Melting point: 110°-111° C.

Similar to the procedures as in Examples 25 to 32, the compounds ofExamples 40-50 as shown in Table 1 and of Examples 51-60 as shown inTable 2 were prepared from the corresponding staring materials. Further,similar to the procedures as in Example 33, the compounds of Examples61-66 as shown in Table 3 were prepared from the corresponding startingmaterials.

                  TABLE 1                                                         ______________________________________                                         ##STR21##                                                                                       Recrystal-        Melting                                  Example            lization  Crystal point                                    No.     R.sup.1    solvent   form    (°C.)                             ______________________________________                                        40      Methyl     Methylene Colorless                                                                             120-122                                                     chloride- needle                                                              n-hexane                                                   41      Isobutyl   Ethyl     Colorless                                                                             133-134                                                     acetate-  flake                                                               n-hexane                                                   42      3-Chloro-  Ethyl     White   122-123                                          propyl     acetate-  powder                                                              n-hexane                                                   43      4-         Ethyl     Colorless                                                                             128-130                                          Bromobutyl acetate-  needle                                                              n-hexane                                                   44      Cyclo-     Ethyl     Colorless                                                                             141-142                                          hexylmethyl                                                                              acetate-  needle                                                              n-hexane                                                   45      2-Cyclo-   Ethyl     Colorless                                                                             149-150                                          hexenyl    acetate-  needle                                                              n-hexane                                                   46      Allyl      Ethyl     Colorless                                                                             101-103                                                     acetate-  needle                                                              n-hexane                                                   47      2-Propynyl Ethyl     Colorless                                                                             129-131                                                     acetate-  flake                                                               n-hexane                                                   48      Geranyl    n-hexane  Colorless                                                                             78-80                                                                 needle                                           49      Cinnamyl   Ethyl     Colorless                                                                             157-159                                                     acetate-  needle                                                              n-hexane                                                   50      3-Allyloxy-                                                                              Ethyl     White   113-114                                          benzyl     acetate-  powder                                                              n-hexane                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR22##                                                                                       Recrystal-        Melting                                  Example            lization  Crystal point                                    No.     R.sup.1    solvent   form    (°C.)                             ______________________________________                                        51      4-allyloxy-                                                                              Ethyl     Colorless                                                                             108-113                                          benzyl     acetate-  needle                                                              n-hexane                                                   52      4-Methoxy- Ethanol   Colorless                                                                             163-164                                          benzyl               flake                                            53      3-Allyl-4- Ethyl     White   121-122                                          hydroxy-   acetate-  powder                                                   benzyl     n-hexane                                                   54      3,4-       Ethyl     Colorless                                                                             126-128                                          Dimethyl-  acetate-  needle                                                   benzyl     n-hexane                                                   55      Naphthyl-  Ethyl     Colorless                                                                             157-158                                          methyl     acetate-  needle                                                              n-hexane                                                   56      3-(Phthal- Ethyl     White   127-129                                          imido-2-   acetate-  powder                                                   yl)propyl  n-hexane                                                   57      Ethoxy-    Ethyl     White   103-104                                          carbonyl-  acetate-  powder                                                   methyl     n-hexane                                                   58      Phenyl     Ethyl     Colorless                                                                             182-184                                                     acetate-  needle                                                              n-hexane                                                   59      4-Fluoro-  Ethyl     Colorless                                                                             188-190                                          phenyl     acetate-  plate                                                               n-hexane                                                   60      3,4-       n-Hexane  Pale    134-137                                          Dimethoxy-           yellow                                                   phenyl               powder                                           ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR23##                                                                                             Recrystal-    Melting                                Example                  lization                                                                             Crystal                                                                              point                                  No.     R.sup.2  R.sup.3 solvent                                                                              form   (°C.)                           ______________________________________                                        61      5-       6-Allyl Ethyl  White  63-64                                          Hydroxy          acetate-                                                                             powder                                                                 petroleum                                                                     ether                                                62      6-       7-Allyl Ethyl  Colorless                                                                            77-78                                          Hydroxy          acetate-                                                                             needle                                                                 n-hexane                                             63      6-       5-Allyl Ethyl  White  84-86                                          Hydroxy          acetate-                                                                             powder                                                                 n-hexane                                             64      7-       6-Allyl Ethyl  White  124-126                                        Hydroxy          acetate-                                                                             powder                                                                 n-hexane                                             65      8-       7-Allyl Ethyl  White  65-66                                          Hydroxy          acetate-                                                                             powder                                                                 n-hexane                                             66      7-       6,8-    Isopropyl                                                                            White  89-91                                          Hydroxy  Diallyl ether- powder                                                                 n-hexane                                             ______________________________________                                    

Example 67

2.4 Grams of 5,7-diallyl-3,4-dihydro-6-hydroxy-1-3-(phthalimido-2-yl)propyl!-2(1H)-quinolinone obtained in Example 56 and1 ml of hydrazine monohydrate were dissolved in 50 ml of ethanol, thisreaction mixture was stirred at 80° C. for 4 hours. The reaction mixturewas cooled, then crystals being precipitated were separated byfiltration, and the filtrate was concentrated, thus obtained residualproduct was extracted with 200 ml of ethyl acetate. The extract waswashed with water, dried with anhydrous magnesium sulfate andconcentrated to obtain residue. This residue was acidified by addingethanol-hydrochloric acid and concentrated to dryness under reducedpressure, there was obtained 1 g (53.3%) of1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonehydrochloride.

White powdery crystals (recrystallized from acetone).

Melting point: 182°-184° C.

Example 68

1.68 Grams of1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonewas dissolved in 100 ml of water, then 10 ml of an aqueous solutioncontaining 1 g of potassium cyanate was added thereto under ice-coolingcondition, and stirred at room temperature for 12 hours. The crystalsthus precipitated were collected by filtration and washed with water,there was obtained 0.5 g (29%) of5,7-diallyl-3,4-dihydro-6-hydroxy-1-(3-ureidopropyl)-2(1H)-quinolinone.

White powdery crystals (recrystallized from ethanol).

Melting point 203°-204° C.

Example 69

1.68 Grams of1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonewas suspended in 100 ml of chloroform, then 5 ml of triethylamine wasadded thereto and stirred for 30 minutes. Under ice-cooling condition, 2ml of chloroacetyl chloride was added little by little and stirred for 5hours. The reaction mixture was washed with water, an aqueous solutionsaturated with sodium hydrogen carbonate and an aqueous solutionsaturated with sodium chloride, and dried with anhydrous magnesiumsulfate, then concentrated under reduced pressure, there was obtained 1g (53%) of1-(3-chloroacetylaminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.White powdery crystals (recrystallized from ethyl acetate-n-hexane).Melting point: 152°-154° C.

In place of chloroacetyl chloride used in Example 69, 2.4 g ofp-toluenesulfonyl chloride was used, there was prepared compound ofExample 70 as follows.

Example 70

5,7-Diallyl-3,4-dihydro-6-hydroxy-1-3-(p-toluenesulfonylamino)propyl!-2(1H)-quinolinone. White powderycrystals (recrystallized from diethyl ether). Melting point: 120°-121°C.

Example 71

1.6 Grams of1-(3-chloropropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneobtained in Example 42 was dissolved in 100 ml of acetonitrile, then 2 gof sodium iodide was added thereto, stirred at 80° C. for 30 minutes andcooled. To this reaction mixture was added 2 ml of triethylamine and 2 gof piperidine and was further stirred at 80° C. for 4 hours, then thereaction mixture was concentrated under reduced pressure, extracted withethyl acetate. The extract was washed with water, dried andconcentrated. Thus obtained oily product was subjected to purication bypassing it through a silica gel column chromatography by using methylenechloride-methanol (50:1) as the eluent, there was obtained 0.96 g (52%)of 5,7-diallyl-3,4-dihydro-6-hydroxy-1-3-(piperidinopropyl)!-2(1H)-quinolinone.

Colorless granular crystals (recrystallized from ethylacetate-n-hexane). Melting point: 129°-130° C.

By using suitable starting materials and by using procedures similarlyas in Example 71, there were prepared the compounds of Examples 72-75 asshown in Table 4.

                  TABLE 4                                                         ______________________________________                                         ##STR24##                                                                                       Recrystal-        Melting                                  Example            lization  Crystal point                                    No.     R.sup.1    solvent   form    (°C.)                             ______________________________________                                        72      3-Morpholino-                                                                            Ethyl     Colorless                                                                             141-142                                          propyl     acetate   needle                                           73      3-(1-      Ethanol   Colorless                                                                             201-203                                          Piperazinyl)-        granular                                                 propyl                                                                74      3-(2-Methoxy-                                                                            Ethyl     Colorless                                                                             96-97                                            ethylamino)-                                                                             acetate-  needle                                                   propyl     n-hexane                                                   75      4-(4-      Ethyl     White   147-149                                          Carbamoyl- acetate-  powder                                                   piperidino)-                                                                             n-hexane                                                           butyl                                                                 ______________________________________                                    

Example 76

2 Grams of5,7-diallyl-3,4-dihydro-1-(ethoxy-carbonylmethyl)-6-hydroxy-2(1H)-quinolinoneobtained in Example 57 was dissolved in 100 ml of 1N-sodium hydroxideaqueous solution, and the solution was stirred at 60° C. for 4 hours.Under ice-cooling condition, the reaction mixture was acidified withhydrochloric acid, the crystals thus precipitated were collected byfiltration, washed with water and dried. There was obtained 0.8 g (53%)of1-(carboxymethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from ethanol).

Melting point: 187°-190° C.

Example 77

1.65 Grams of5,7-diallyl-1-(ethoxy-carbonylmethyl)-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneobtained in Example 57 was dissolved in 50 ml of methanol, then 20 ml of25% ammonia water thereto, the reaction mixture was stirred for 24hours. Then the reaction mixture was concentrated under reducedpressure. The concentrate was extracted with chloroform, washed withwater, dried, then concentrated again under reduced pressure. Thusobtained crude crystals were subjected to purification by passing itthrough a silica gel column and by using methylene chloridemethanol(50:1) as the eluent, there was obtained 1.2 g (80%) of1-(carbamoylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from ethanol).

Melting point: 163°-164° C.

Example 78

3.4 Grams of6-allyloxy-1-(4-allyloxy-3-methoxybenzyl)-3,4-dihydro-2(1H)-quinolinoneobtained in Reference example 13 was reacted and treated similarly as inExample 1, the reaction mixture thus obtained was subjected to flushcolumn chromatography by using ethyl acetate:n-hexane (1:100 to 1:25).The secondary eluted portion was collected and concentrated underreduced pressure. The concentrate was recrystallized from ethylacetate-n-hexane, there was obtained 0.6 g (17.6%) of5-allyl-6-hydroxy-1-(3-allyl-4-hydroxy-5-methoxybenzyl)-3,4-dihydro-2(1H)-quinolinone.White crystalline powder (recrystallized from ethyl acetate-n-hexane).Melting point: 159°-161° C.

Example 79

2.43 Grams of the mixture of5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16was dissolved in 50 ml of dimethylformamide, then 0.6 g of 60% oilysodium hydride was added little by little thereto at room temperature,and stirred at 25° to 40° C. until generation of hydrogen gas wasceased. After the reaction mixture was cooled to room temperature, 1.32g of 1,4-dibromomethylbenzene was added and stirred at room temperaturefor 4 hours. After the reaction was finished, water was added thereto,extracted with ethyl acetate, the extract was washed with water, andaqueous solution saturated with sodium chloride, then dried withanhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, the filtrate was concentrated to obtain 5.9 g (100%) of paleyellow oily product. 3 Grams of this yellow oily product was dissolvedin 50 ml of tetralin, and was reacted and treated similarly as inExample 1, there was obtained 3 g (100%) of 1,4-bis(5,7-diallyl-6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolyl)methyl!-benzene.

Pale yellow powder (recrystallized from ethanol).

Melting point: 213°-215° C.

Example 80

80 Grams of the mixture of5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16was dissolved in 300 ml of dimethylformamide, then 15 g of 60% oilysodium hydride was added little by little thereto at room temperatureand stirred at 25° to 40° C. until generation of hydrogen gas wasceased. After the reaction mixture was cooled to room temperature, 35 gof prenyl chloride was added thereto and stirred at 50° C. for 2 hours,further stirred at room temperature for 8 hours. After finished thereaction, the dimethylformamide was removed by distillation underreduced pressure to obtain the residue. To the residue was added waterand extracted with ethyl acetate. The extract was washed with water andan aqueous solution saturated with sodium chloride, then dried withanhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, and the filtrate was concentrated to obtain pale yellow oilyproduct. This oily product was subjected to separation and purificationby means of a silica gel flush chromatography, by using a mixed solventof ethyl acetate:n-hexane (1:10 to 1:2) as the eluent, there wasobtained 29 g (28.3%) of6-allyloxy-3,4-dihydro-1-prenyl-7-(1-propenyl)-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from ethylacetate-n-hexane). Melting point: 87°-88° C.

¹ H-NMR (CDCl₃, ppm):

1.73 (1H, s), 1.83 (1H, s), 1.90 (3H, d), 2.63 (2H, m), 2.84 (2H, t),4.52-4.55 (4H, m), 5.12-5.17 (2H, m), 5.27-5.47 (2H, m), 6.01-6.21 (2H,m), 6.66 (1H, s), 6.72 (1H, d), 7.01 (1H, s).

Example 81

5-Allyloxy-1-{3- 4-(3-chlorophenyl)-1-piperazinyl!propyl}-3,4-dihydro-2(1H)-quinolinone was reacted and treated similarly as inExample 1. Thus obtained crude product was subjected to purification bymeans of a silica gel chromatography, thus obtained product wasdissolved in ethanol and acidified with hydrochloric acid, concentratedunder reduced pressure to dryness, there was obtained6-allyl-5-hydroxy-1-{3-4-(3-chlorophenyl)-1-piperazinyl!propyl}-3,4-dihydro-2(1H)-quinolinone.hydrochloride.

Colorless needle crystals (recrystallized from ethanolisopropyl ether).Melting point: 200°-204° C.

Example 82

1-(3-Chlorophenyl)piperazine was used as cyclic amine and was reactedand treated similarly as in Example 71. Thus obtained crude product wassubjected to purification by means of a silica gel chromatography, thereis obtained 5,7-diallyl-1-{3-4-(3-chlorophenyl)-1-piperazinyl!propyl}-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from ethylacetate-n-hexane). Melting point: 117.5°-118.5° C.

Example 83

8-Allyl-7-hydroxy-3-prenyl-2(1H)-quinolinone obtained in Example 4 wasreacted and treated similarly as in Example 39, there was obtained6,8-diallyl-7-hydroxy-3-prenyl-2(1H)-quinolinone.

Pale yellow needle-like crystals (recrystallized from acetone). Meltingpoint: 241°-244° C.

Example 84

1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1.9 g) prepared in Example 43 was dissolved in acetonitrile (50 ml),then n-butylamine (2 ml) was added and stirred at 80° C. for 4 hours.The reaction mixture was extracted with ethyl acetate, and the extractwas washed with an aqueous solution saturated with sodium bicarbonate,next with water, then concentrated under reduced pressure. Thus obtainedoily residual product was dissolved in ethanol, acidified by addingoxalic acid, then concentrated to dryness, and recrystallized fromacetone, there was obtained of1-(4-n-butylaminobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.oxalatein 35% yield.

White powdery product (recrystallized from acetone).

Melting point: 194°-197° C. (decomposed).

By reacting1-(4-bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonewith suitable amines or cyclic amines similarly as in Example 84, therewere obtained compounds of Examples 85 to 87 as follows.

Example 85

5,7-Diallyl-3,4-dihydro-6-hydroxy-1-4-(2-hydroxy-1,1-dimethyl)ethylamino!butyl-2-(1H)-quinolinone. oxalate.

White powdery crystals (recrystallized from acetone).

Melting point: 129°-132° C.

Example 86

5,7-Diallyl-1-(4-diethylaminobutyl)-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.oxalate

White powdery crystals (recrystallized from acetone).

Melting point: 191°-193° C.

Example 87

5,7-Diallyl-3,4-dihydro-6-hydroxy-1- 4-(imidazol-1-yl)butyl!-2-(1N)-quinolinone.oxalate

White powdery crystals (recrystallized from acetone).

Melting point: 125°-128° C.

Example 88

1-(3-Chloropropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneand 1H-1,2,4-triazole were reacted and treated similarly as in Example71, there was obtained 5,7-diallyl-3,4-dihydro-6-hydroxy-1-3-(1,2,4-triazol-4-yl)propyl!-2(1H)-quinolinone.

White powdery crystals (recrystallized from acetone).

Melting point: 129°-132° C.

By reacting a quinolinone compound having a haloalkyl group at1-position with an ester of amino acid, there were prepared compounds ofExamples 89 to 90 as follows.

Example 89

1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1.9 g) was dissolved in 50 ml of acetonitrile, then 2 g of L-leucinemethyl ester hydrochloride and 5 ml of triethylamine were added thereto,and stirred at 80° C. for 4 hours. The reaction mixture was extractedwith ethyl acetate, the extract was washed with an aqueous solutionsaturated with sodium bicarbonate, next with water, then wasconcentrated under reduced pressure. Thus obtained oily residual productwas subjected to purification by means of a silica gel columnchromatography, then recrystallized from acetone, there was obtained 1-4-(1-methoxycarbonyl-4-methyl)pentylamino!butyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.hydrochloride.

White powdery crystals (recrystallized from acetate).

Melting point: 184°-186° C.

Example 90

5,7-Diallyl-3,4-dihydro-1-4-(1-methoxy-carbonyl-4-methyl)pentylamino!butyl-6-hydroxy-2(1H)-quinolinone(1 g) obtained in Example 89 was dissolved in 10 ml of methanol and 10ml of 1N-sodium hydroxide aqueous solution, then this mixture wasstirred at 70° C. for 1 hour. After cooling, the reaction mixture wasacidified by adding hydrochloric acid, further the acidified reactionmixture was made basic by adding 25% ammonia water. The reaction mixturewas concentrated under reduced pressure to dryness, thus obtained solidresidual product was subjected to extraction by means of a Soxhlet'sextractor with chloroform as the solvent. The chloroform extract wasconcentrated under reduced pressure to dryness, then recrystallized fromacetone, there was obtained 1-4-(1-carboxy-4-methyl)pentylamino!butyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from acetone).

Melting point: 166°-174° C. (decomposed).

Example 91

1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1.9 g) was dissolved in 50 ml of acetonitrile, then 2 g ofN-methylglycine ethyl ester hydrochloride and 5 ml of triethylamine wereadded thereto, and stirred at 80° C. for 4 hours. The reaction mixturewas extracted with ethyl acetate, the extract was washed with an aqueoussolution saturated with sodium bicarbonate, next with water, thenconcentrated under reduced pressure. Thus obtained oily residual productwas subjected to purification by means of a silica gel columnchromatography, then dissolved in 10 ml of methanol and 10 ml of1N-sodium hydroxide aqueous solution, and stirred at 70° C. for 1 hour.After the reaction mixture was cooled, the mixture was acidified byadding hydrochloric acid, further the acidified reaction mixture wasmade basic by adding 25% ammonia water. This reaction mixture wasconcentrated under reduced pressure to dryness, thus obtained solidresidual product was subjected to extraction by means of Soxhlet'sextractor with chloroform as the solvent. The chloroform extract wasconcentrated under reduced pressure to dryness, and recrystallized fromacetone, there was obtained 1- 4-(N-carboxymethyl-N-methyl-amino)butyl!-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from acetone).

Melting point: 174°-181° C. (decomposed).

Example 92

1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1.9 g) was dissolved in 50 ml of acetonitrile, then 2 g of L-prolinemethyl ester hydrochloride and 5 ml of triethylamine were added thereto,and stirred at 80° C. for 4 hours. The reaction mixture was extractedwith ethylacetate, the extract was washed with an aqueous solutionsaturated with sodium bicarbonate, next with water, then concentratedunder reduced pressure. The obtained oily residual product was subjectedto purification by means of a silica gel column chromatography, thendissolved in 10 ml of methanol and 10 ml of 1N-sodium hydroxide aqueoussolution, and stirred at 70° C. for 1 hour. After the reaction mixturewas cooled, the mixture was acidified by adding hydrochloric acid,further the acidified reaction mixture was made basic by adding 25%ammonia water. This reaction mixture was concentrated under reducedpressure to dryness, thus obtained solid residual product was subjectedto extraction by means of Soxhlet's extractor with chloroform as thesolvent. The chloroform extract was concentrated under reduced pressureto dryness, and recrystallized from acetone, there was obtained 1-4-(2-carboxy-1-pyrrodinyl)butyl!-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powdery crystals (recrystallized from acetone).

Melting point: 147°-151° C.

Example 93

Mixture of1-(4-bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1.5 g), triethylphosphite (3 ml) and sodium iodide (100 mg) was stirredat 150° C. for 4 hours. After the reaction mixture was cooled, thereaction mixture was subjected to purification by passing it through asilica gel column chromatography by using ethyl acetate-n-hexane as theeluent, then recrystallized from water-containing ethanol, there wasobtained5,7-diallyl-1-(4-diethoxy-phosphorylbutyl)-3,4-dihydro-6-hydroxy-2(1H)-quinolinonein 64% yield.

White powdery product (recrystallized from water-containing ethanol).

Melting point: 38°-42° C.

Example 94

5,7-Diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (24.3 g) obtained inExample 26 was dissolved in 100 ml of 3,4-dihydro-2H-pyran, then 1 ml ofconcentrated hydrochloric acid was added thereto and stirred at 60° C.for 8 hours. The reaction mixture was cooled, and neutralized with 10%sodium bicarbonate solution, then extracted with ethyl acetate. Theextract was washed with an aqueous solution saturated with sodiumbicarbonate, and concentrated under reduced pressure. Recrystallizedfrom ethyl acetate-n-hexane, there was obtained 14 g (58%) of5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone.

White crystalline powder (recrystallized from ethyl acetate-n-hexane).

Melting point: 119°-120° C.

Example 95

5,7-Diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone(6.47 g) obtained in Example 94 was dissolved in 100 ml ofdimethylformamide, then 1.2 g of 60% oily sodium hydride was addedlittle by little thereto at room temperature and stirred untilgeneration of hydrogen gas was ceased. Then, 5 ml of 2-bromoethylcyanidewas added thereto and stirred at room temperature for 4 hours. Afterfinished the reaction, water was added to the reaction mixture andextracted with ethyl acetate. The extract was washed with water, and anaqueous solution saturated with sodium chloride in this order, thendried with anhydrous magnesium sulfate. The magnesium sulfate wasremoved by filtration, and the filtrate was concentrated to obtain paleyellow oily product. This oily product was subjected to purification bymeans of a silica gel column chromatography (by using methylenechloride-ethyl acetate=4:1 as the eluent).

Recrystallized from ethyl acetate-n-hexane there was obtained1-(2-cyanoethyl)-5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone.

Colorless needle crystals (recrystallized from ethyl acetate-n-hexane).

Melting point: 93°-94° C.

Example 96

1-(2-Cyanoethyl)-5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone(1 g) obtained in Example 95 was dissolved in 50 ml of methanol, then6N-hydrochloric acid was added thereto and stirred at 60° C. for 30minutes so as to remove the tetrahydropyranyl group, and concentratedunder reduced pressure to dryness. Thus obtained residual product wassubjected to purification by means of a silica gel columnchromatography, then recrystallized from ethyl acetate-n-hexane, therewas obtained1-(2-cyanoethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

Colorless needle-like crystals (recrystallized from ethylacetate-n-hexane).

Melting point: 114°-116° C.

Suitable halogenated compounds and5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinonewere reacted and treated similarly as in Examples 95 or 96, there wereprepared compounds of Examples 97 to 108 as shown in Table 5 as follows.

                  TABLE 5                                                         ______________________________________                                         ##STR25##                                                                                        Recrystal-       Melting                                  Example             lization  Crystal                                                                              point                                    No.     R.sup.1     solvent   form   (°C.)                             ______________________________________                                        97      1-Ethyl-    Ethyl     Colorless                                                                            108-109                                                      acetate-  needles                                                             n-hexane                                                  98      1-Isopropyl-                                                                              Ethyl     Colorless                                                                            149-150                                                      acetate-  needles                                                             n-hexane                                                  99      1-n-Butyl-  Ethanol   Colorless                                                                            116-117                                                                plates                                          100     1-(3-       Ethyl     Colorless                                                                            119-120                                          Methylbutyl)-                                                                             acetate-  plates                                                              n-hexane                                                  101     1-Octyl-    Ethyl     Colorless                                                                            102-103                                                      acetate-  needles                                                             n-hexane                                                  102     1-Dodecyl-  Ethyl     Colorless                                                                            90-91                                                        acetate-  flakes                                                              n-hexane                                                  103     1-(2-Acetyloxy-                                                                           Ethyl     Colorless                                                                            87-88                                            ethyl)-     acetate-  flakes                                                              n-hexane                                                  104     1-(4-Acetyloxy-                                                                           Ethyl     Colorless                                                                            107-108                                          butyl)-     acetate-  flakes                                                              n-hexane                                                  105     1-(4-Methoxy-                                                                             Ethyl     Colorless                                                                            84-86                                            carbonylbutyl)-                                                                           acetate-  flakes                                                              n-hexane                                                  106     1-(5-Ethoxy-                                                                              Ethyl     Colorless                                                                            79-80                                            carbonyl-   acetate-  flakes                                                  pentyl)-    n-hexane                                                  107     1-(4-Methoxy-                                                                             Ethyl     White  155-157                                          carbonyl-   acetate-  powder                                                  benzyl)-                                                              108     1-(2-Ethoxy-                                                                              Diethyl   White  127-129                                          carbonylethyl)-                                                                           ether-    powder                                                              n-hexane                                                  ______________________________________                                    

Example 109

1-(2-Acetyloxyethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1 g) prepared in Example 103 was hydrolyzed similarly as in Example 76,there was obtained5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-hydroxyethyl)-2(1H)-quinolinone.

White powdery crystals (recrystallized from ethyl acetate-n-hexane).

Melting point: 106°-108° C.

Example 110

1-(2-Acetyloxybutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone(1 g) prepared in Example 104 was hydrolyzed similarly as in Example109, there was obtained5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-hydroxybutyl)-2(1H)-quinolinone.

Colorless granular crystals (recrystallized from ethylacetate-n-haxane).

Melting point: 115°-116° C.

Example 111

5,7-Diallyl-3,4-dihydro-6-hydroxy-1-(4-methoxycarbonylbenzyl)-2(1H)-quinolinone(1 g) prepared in Example 107 was hydrolyzed similarly as in Example109, there was obtained1-(4-carboxybenzyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.White powdery crystals (recrystallized from methanol).

Melting point: 242°-246° C.

Example 112

5,7-Diallyl-3,4-dihydro-6-hydroxy-1-(2-ethoxycarbonylethyl)-2(1H)-quinolinone(1 g) prepared in Example 108 was hydrolyzed similarly as in Example109, there was obtained1-(4-carboxyethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.

White powder crystals (recrystallized from ethyl acetate-n-hexane).Melting point: 174°-176° C.

Example 113

1-(4-Carboxymethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonewas dissolved in 50 ml of methanol, then under ice-cooling condition, anmethanol solution of potassium hydroxide was added thereto so as toadjust pH=8 to 9, then concentrated to dryness. Recrystallized frommethanol, there was obtained sodium(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)acetate.Pale yellow powder crystals (recrystallized from methanol).

Melting point: 212°-221° C. (decomposed).

Similar to as in Example 113, there were prepared compounds of Examples114 and 115 as follows.

Example 114

1-(4-Carboxybenzyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinonewas treated similarly as in Example 113, there was obtained sodium4-(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)-methylbenzoate.

Pale yellow powdery crystals (recrystallized from acetone).

Melting point: 268°-285° C. (decomposed).

Example 115

Sodium2-(5,7-Diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)propionate.

Pale yellow powdery crystals (recrystallized from acetone).

Melting point: 201°-203° C. (decomposed).

Example 116

2-(4-Chlorobutyl)-1-cyclohexyl-1H-1 ,2,3,4-tetrazole was reacted with5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy-2(1H)-quinolinone inaccordance with methods of preparation similarly as in Examples 95 and96, there was obtained 1-4-(1-cyclohexyl-1H-1,2,3,4-tetrazol-2-yl)butyl-5,7-diallyl-3,4,-dihydro-2(1H)-quinolinone.

Pale yellow powdery crystals (recrystallized from ethanol).

Melting point: 121°-124° C.

5,7-Diallyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone obtained inExample 27 was reacted with a suitable corresponding starting material,similarly as in Example 16, there were obtained compounds of Examples117 to 120 as follows.

Example 117

6-Acetyloxy-5,7-diallyl-3,4-dihydro-1-prenyl-2(1H)-quinolinone.

Boiling point: 140°-150° C./0.4 mmHg

Example 118

6-(3-Carboxypropionyloxy)-5,7-diallyl-3,4-dihydro-1-prenyl-2(1H)-quinolinone.

White powder (recrystallized from acetone-water).

Melting point: 148°-151° C.

Example 119

5,7-Dialyl-3,4-dihydro-6-(3-nicotinoyloxy)-1-prenyl-2(1H)-quinolinone-hydrochloride.

Pale yellow powder crystals (recrystallized from acetone-water).

Melting point: 142°-151° C.

Example 120

Sodium 5,7-diallyl-3,4-dihydro-1-prenyl-2(1H)-quinolinone-6-oxide.

Reddish orange powder crystals (recrystallized from methanol)

Melting point: 110°-117° C. (decomposed).

Pharmacological tests

Pharmacological tests of the cyclic amide derivatives of the presentinvention relating to in vitro test for determination of the activityfor inhibiting the formation of lipid peroxides by ultravioletradiation, and the activity for scavenging radicals; and in vivo testfor determination of the activity for photoprotection were conducted asfollows:

(A) The activity for inhibiting the formation of lipid peroxides

The activity for inhibiting the formation of lipid peroxides which areincreasingly formed by exposed to the ultraviolet-B radiation to theskin homogenate of guinea pig was determined by a procedure ofthiobarbituric acid method (TBA method).

Unsaturated fatty acids of bioconstituents are oxidized finally tomalondialdehyde by the actions of various radicals formed due to exposedto the ultraviolet rays. The activity for inhibiting the formation oflipid peroxides can be evaluated by degree of decreasing the opticalabsorbance of the condensate of thus formed malondialdehyde withthiobarbituric acid, by adding a test sample of the cyclic amidederivative of the present invention to the homogenate. In this test,vitamin E which was used as the reference compound, is known that itpossesses antioxidation activity, activity for scavenging radicals andactivity for inhibiting the formation of lipid peroxides.

The test was conducted by applying OGURA's method cf. Kurume IgakukaiZasshi (Journal of Kurume Medical Academy (Japan)), 1984, Vol. 47, pp.223-236!. That is, the hairs covering in the back of an albino guineapig (Hartley strain, female) were clipped by using an electric hairclippers under anesthesia. After the enucleation of the hair clippedportion of the skin, the subcutaneous tissue of this skin was removed incold physiological saline. Distilled water in an amount of 9 times byweight of the skin tissue was added to this skin subcutaneous tissue,then was subjected to homogenation and centrifugation (600 g, for 5minutes) to obtain the supernatant liquid. 5 Microliters each of testsample solutions of various concentrations was added to 0.5 ml each ofthe supernatant liquid, then the ultraviolet ray in the intensity of 9.5mW/cm² was irradiated for 60 minutes by using fluorescent lamps (TOSHIBAFL-20SE, manufactured by Toshiba Corporation) as a light source. As tothe reference sample solution, the solvent for dissolution of the testcompound was used in place of the test sample solution. Afterultraviolet radiation, the amount of lipid peroxide being formed in thesample solution (TBA value) was measured by TBA method (cf. AnalyticalBiochemistry, 1979, Vol. 95, pp. 351-358), and the inhibition rate oflipid peroxide formation shown by the test sample was calculated by thefollowing formula: ##EQU1##

Test results of inhibition rate of lipid peroxide formation of the testcompounds in the concentration of 10⁻⁴ M are shown in Table 6. Vitamin E(α-tocopherol) used as the reference compound in the same concentration(10⁻⁴ M) showed about 77-79% of the inhibition as shown by the testsamples.

                  TABLE 6                                                         ______________________________________                                                Inhibition rate        Inhibition rate                                Example of lipid peroxide                                                                           Example  of lipid peroxide                              No.     formation (%) No.      formation (%)                                  ______________________________________                                        10      82            51       95                                             11      70            52       100                                            17      85            53       95                                             20      81            54       96                                             25      78            57       78                                             26      80            60       83                                             27      82            62       81                                             28      80            63       81                                             32      87            65       79                                             33      83            67       75                                             38      80            68       68                                             39      82            69       78                                             40      84            74       68                                             41      96            76       68                                             44      100           78       95                                             45      95            80       95                                             46      95            86       71                                             48      95            93       73                                             50      89                                                                    ______________________________________                                    

As can be seen from the test results in Table 6, cyclic amidederivatives of the present invention inhibit the formation ofthiobarbituric acid reaction products formed in the skin of guinea pigby the irradiation of ultraviolet rays. Thus, cyclic amide derivativesof the present invention inhibit the actions of active oxygen speciesand of lipid peroxides species which are formed increasingly byultraviolet radiation. Therefore, cyclic amide derivatives of thepresent invention can be expected to the usefulness of agents forpreventing and treating various diseases caused by active oxygen speciesformed increasingly by ultraviolet radiation, and preventive agents andcosmetics, quasi-drugs and medicines for external use for preventingsunburn, winkles and melasma caused by the sunlight.

(B) The activity for inhibiting skin erythema which is caused byultraviolet radiation

This test is an experimental model of quantitative evaluation method formeasuring protective effect of the test compound relating to the skinerythema reaction (sunburn) caused by ultraviolet radiation (Cf. TheJournal of Dermatology, Vol. 17, pp. 595-598, 1990).

The hairs covering in the back of albino guinea pig (Hartley strain,female, 7-8 week age) were shaved by using an electric hair clippers anda shaver. In the next day, the guinea pig was fixed in Bowlman's cage,then a light shield tape (adhesive plaster for patch test), having 4round holes of 1.5 cm in diameter was adhered on the hair clippedportion so as to provide 4 sites (round holes) to be exposed to theultraviolet rays. The solvent for dissolving the test compound of 10 μlwas topically applied to a site (control site to be exposed), and 10 μleach of the test sample solutions in predetermined concentrations wastopically applied to the remaining three sites (test sites to beexposed). 30 Minutes later the applications, the ultraviolet rays in theintensity of 1.3-1.5 mW/cm² was irradiated for 30 minutes by usingfluorescent lamps (TOSHIBA FL-20SE) as the light source. 24 Hours laterultraviolet radiation, the degrees of flush (Δa value) of the controlsite and the test sites applied with the test sample solutions weremeasured by using a color difference meter (OFC-300A type, manufactureby NIPPON DENSHOKU KOGYO CO., LTD.) and the rate of activity forinhibiting the skin erythema of the test compound was calculated by thefollowing formula: ##EQU2##

Each one of the test sample solutions was prepared by dissolving eachtest compounds in three kinds of concentrations within 0.1 to 10%, andapplied.

Rate of activity for inhibiting the skin erythema by the test samplesolutions of 3% concentration of the test compound are shown in Table 7as follows, and the figures in parentheses represent 50% inhibitoryconcentration (IC₅₀ value; concentration in %) of the test compound.

                  TABLE 7                                                         ______________________________________                                                Rate of activity       Rate of activity                                       for inhibiting the     for inhibiting the                                     skin erythema (%)      skin erythema (%)                              Example (IC.sub.50 ; concen-                                                                        Example  (IC.sub.50 ; concen-                           No.     tration in %) No.      tration in %)                                  ______________________________________                                        10      38                67     31                                           20      37                68     43                                           26      36                71     45                                           27      60       (1.3)    72     33                                           28      30                76     50     (3.1)                                 33      18       (9.4)    77     50     (2.7)                                 35      41       (5.9)    84     31                                           36      26       (9.8)    85     39                                           37      39       (7.7)    87     28                                           39      42       (4.7)    88     37                                           40      23       (5.6)    101    37                                           41      57       (2.0)    102    57     (3.7)                                 42      45                104    31                                           44      63       (1.6)    105    44                                           48      37                107    44                                           50      36                110    44                                           60      27                113    52     (2.5)                                 63      35       (6.5)    115    33                                           ______________________________________                                    

As can be seen from the test results in Table 7, cyclic amidederivatives of the present invention inhibit the skin erythema reactioncaused by ultraviolet radiation in guinea pig. Thus, cyclic amidederivatives of the present invention are useful as agent for protectingvarious disease including skin cancer caused by the ultraviolet rays,and also these derivatives are useful as agents for protecting sunburn,wrinkles and melasma caused by the sunlight, cosmetics, quasi-drugs andmedicines for external use.

(C) The activity for preventing the lens opacity

The test was conducted by referring to a method of Abraham Spector (cf.Current Eye Research, Vol. 2, 1993, pp. 163-179).

The lens samples obtained from rat (Wistar strain, male, 6-10 week age)were placed on 24-well plate, and were cultured in DEMEM (Dulbecco'smodified Eagle's medium manufactured by Nissui Pharmaceutical Co., Ltd.)at 37° C. overnight, a 5% CO₂ environment was used. Under dissectingmicroscope observation, the lens samples having transparency were onlyselected to use the test. Thus selected lens samples were transferred tomidium (1 ml) in which the test compound was dissolved. (As to thereference test, the medium without containing the test compound wasused.) The ultraviolet rays in the intensity of 8.8 mW/cm² wasirradiated for 60 minutes by using a fluorescent lamp (TOSHIBA FL-20SE)to the lens samples. After the irradiation, the medium was replaced tonew medium containing the test compound and further cultured overnight.The medium without the test compound was replaced everyday during 3days. By using a dissecting microscope, opacity of the lens samples wereobserved. The degrees of opacity of the lens samples was determined bydeviding the field of vision into 8 fields as follows: Score 0:transparent; Score 1: some loss of transparency; and Score 2: completelyopaque. Rate of activity for preventing the lens opacity was calculatedfrom the following formula: ##EQU3##

Test results of rate of the activity for preventing the lens opacitygiven by test compounds in the concentration of 10⁻⁴ M are shown inTable 8. The cyclic amide derivatives or salts thereof of the presentinvention show about 10 times higher effect as compared with that ofshown by vitamin C.

                  TABLE 8                                                         ______________________________________                                                    Concentration of                                                                          Rate of the activity                                  Example     test compound                                                                             for preventing lens                                   No.         (10.sup.-4 M)                                                                             opacity (%)                                           ______________________________________                                         41         1           55                                                     67         1           40                                                     98         1           45                                                    101         1           55                                                    103         1           57                                                    109         1           66                                                    115         1           63                                                    Vitamin C   10          84                                                    Vitamin C   1           -11                                                   ______________________________________                                    

As can be seen from Table 8, the cyclic amide derivatives of the presentinvention prevent the opacity of the lens of rat caused by irradiationof the ultraviolet rays. From these test results, the cyclic amidederivatives and salts thereof of the present invention are useful asagent for preventing cataract.

We claim:
 1. A pharmaceutical composition containing a pharmaceuticallyacceptable carrier and, as the effective ingredient, a cyclic amidederivative or a salt thereof represented by the general formula (1):##STR26## wherein R² is a hydroxyl group, a lower alkenyloxy group, aphenyl-lower alkenyloxy group, a cycloalkenyloxy group, atetrahydropyranyloxy group, or a pyridyloxy group;R³ is a lower alkenylgroup; Z is a group of --CH₂ -- or a group of --CH═CH--; n is an integerof 1 to 3; m is 0 or 1; provided that when Z is a group of --CH₂ --,then m is 1 and when Z is a group of --CH═CH--, then m is 0; R¹ is ahydrogen atom, an alkyl group, an alkenyl group, a phenyl-lower alkenylgroup, a cycloalkyl-lower alkyl group, a phenyl group which may have, inthe phenyl ring, one or more substituents selected from the groupconsisting of a lower alkoxy group and a halogen atom, a hydroxylgroup-substituted alkyl group, a halogen-substituted lower alkyl group,a cycloalkenyl group; a lower alkynyl group, a phenyl-lower alkyl groupwhich may have, in the phenyl ring, 1 to 3 substituents selected fromthe group consisting of a lower alkenyloxy group, a lower alkoxy group,a lower alkenyl group, a hydroxyl group, a lower alkyl group, a carboxylgroup, a lower alkoxycarbonyl group and a group of the formula:##STR27## a naphthyl-substituted lower alkyl group, aphthalimido-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a group of the formula:##STR28## (wherein A is a lower alkylene group; R⁴ and R⁵ are the sameor different, and are each a hydrogen atom, a carbamoyl group, a loweralkanoyl group which may have one or more halogen atoms, aphenylsulfonyl group which may have, in the phenyl ring, one or morelower alkyl groups as substituents, a lower alkoxy-lower alkyl group, alower alkyl group, a hydroxyl group-substituted lower alkyl group, alower alkoxycarbonyl group-substituted lower alkyl group, or acarboxy-substituted lower alkyl group, further R⁴ and R⁵ may form a 5-or 6-membered saturated or unsaturated heterocyclic group by combiningto each other, together with the adjacent nitrogen atom being bondedthereto, further with or without other nitrogen atom or oxygen atom;said heterocyclic group may have one or more substituents, selected fromthe group consisting of a carbamoyl group, a carboxyl group, acycloalkyl group and a phenyl group which may have one or more halogenatoms as substituents in the phenyl ring); a lower alkanoyloxy-loweralkyl group, a cyano group-substituted lower alkyl group, a group of theformula: ##STR29## (wherein A is a lower alkylene group; R⁹ and R¹⁰ arethe same or different, and are each a hydrogen atom or a lower alkylgroup), a carboxy-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group or a carbamoyl-substitutedlower alkyl group provided that when n is 1, Z is a group of --CH═CH--and R¹ is a hydrogen atom, then R² should not be a hydroxyl group, alower alkanoyloxy group, a tetrahydropyranyloxy group or a pyridyloxygroup.
 2. The pharmaceutical composition according to claim 1,containing as the effective ingredient, the cyclic amide derivative orsalt thereof represented by the general formula (1),wherein R² is ahydroxyl group or a lower alkenyloxy group; R¹ is an alkyl group, acycloalkyl-lower alkyl group, a carboxy-substituted lower alkyl group, acarbamoyl-substituted lower alkyl group, an alkenyl group, a loweralkanoyloxy-lower alkyl group, a hydroxyl group-substituted alkyl group,a phenyl-lower alkyl group which may have, in the phenyl ring, 1 to 3substituents selected from the group consisting of a lower alkenyloxygroup, a lower alkoxy group, a lower alkenyl group, a hydroxyl group, alower alkyl group, a carboxyl group, a lower alkoxycarbonyl group and agroup of the formula: ##STR30## or a group of the formula: ##STR31##(wherein A is a lower alkylene group; R⁴ and R⁵ are the same ordifferent, and are each a hydrogen atom, a carbamoyl group, a loweralkanoyl group which may have halogen atom(s), a phenylsulfonyl groupwhich may have, in the phenyl ring, lower alkyl group(s) assubstituent(s), a lower alkoxy-lower alkyl group, a lower alkyl group, ahydroxyl group-substituted lower alkyl group, a lower alkoxycarbonylgroup-substituted lower alkyl group, or a carboxy-substituted loweralkyl group; further, R⁴ and R⁵ may form a 5- or 6-membered saturated orunsaturated heterocyclic group by combining to each other, together withthe adjacent nitrogen atom being bonded thereto, further with or withoutother nitrogen atom or oxygen atom; said heterocyclic group may have,substituent(s) selected from the group consisting of a carbamoyl group,a carboxyl group, a cycloalkyl group and a phenyl group which may havehalogen atom(s) as substituent(s) in the phenyl ring); and n is 2 or 3.3. The pharmaceutical composition according to claim 1, wherein theeffective ingredient is the cyclic amide derivative or salt thereofrepresented by the general formula (1), selected from the groupconsistingof:1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-methylpropyl)-2(1H)-quinolinone;1-(cyclohexylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)acetic acidsodium salt;1-(carbamoylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone;2-(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)propionicacid sodium salt;1-isopropyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;1-octyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;1-(2-acetyloxyethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-hydroxyethyl)-2-(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(4-methoxybenzyl)-2(1H)-quinolinone;1-(3-allyloxybenzyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneand1-(cyclohexylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.4. A cyclic amide derivative or a salt thereof represented by thegeneral formula (2): ##STR32## wherein R² is a hydroxyl group, a loweralkenyloxy group, a phenyl-lower alkenyloxy group, a cycloalkenyloxygroup, a tetrahydropyranyloxy group, or a pyridyloxy group;R³ is a loweralkenyl group; Z is, a group of --CH₂ -- or a group of --CH═CH--; n isan integer of 1 to 3; m is 0 or 1; provided that when Z is a group of--CH₂ --, then m is 1 and when Z is a group of--CH═CH--, then m is 0; R¹is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl-loweralkenyl group, a cycloalkyl-lower alkyl group, a phenyl group which mayhave, in the phenyl ring, one or more substituents selected from thegroup consisting of a lower alkoxy group and a halogen atom, a hydroxylgroup-substituted alkyl group, a halogen-substituted lower alkyl group,a cycloalkenyl group; a lower alkynyl group, a phenyl-lower alkyl groupwhich may have, in the phenyl ring, 1 to 3 substituents selected fromthe group consisting of a lower alkenyloxy group, a lower alkoxy group,a lower alkenyl group, a hydroxyl group, a lower alkyl group, a carboxylgroup, a lower alkoxy-carbonyl group and a group of the formula:##STR33## a naphthyl-substituted lower alkyl group, aphthalimido-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a group of the formula:##STR34## (wherein A is a lower alkylene group; R⁴ and R⁵ are the sameor different, and are each a hydrogen atom, a carbamoyl group, a loweralkanoyl group which may have one or more halogen atoms, aphenylsulfonyl group which may have, in the phenyl ring, one or morelower alkyl groups as substituents, lower alkoxy-lower alkyl group, alower alkyl group, a hydroxyl group-substituted lower alkyl group, alower alkoxycarbonyl group-substituted lower alkyl group, or acarboxy-substituted lower alkyl group; further R⁴ and R⁵ may form a 5-or 6-membered saturated or unsaturated heterocyclic group by combiningto each other, together with the adjacent nitrogen atom being bondedthereto, further with or without other nitrogen atom or oxygen atom;said heterocyclic group may have one or more substituents selected fromthe group consisting of a carbamoyl group, a carboxyl group, acycloalkyl group and a phenyl group which may have one or more halogenatoms as substituents in the phenyl ring);a lower alkanoyloxy-loweralkyl group, a cyano group-substituted lower alkyl group, a group of theformula: ##STR35## (wherein A is a lower alkylene group; R⁹ and R¹⁰ arethe same or different, and are each a hydrogen atom or a lower alkylgroup), a carboxy-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group or a carbamoyl-substitutedlower alkyl group; provided that(i) when n is 1, R² is OH, Z is a groupof --CH═CH-- or a group of --CH₂ -- and m is 1, then R¹ should not be ahydrogen atom, a lower alkyl group, a lower alkenyl group, aphenyl-lower alkyl group, a phenyl group or a piperidinyl-lower alkylgroup; (ii) when Z is a group of --CH═CH-- or a group of --CH₂ -- and mis 1, and R² is a hydroxyl group which is substituted at 7-position inthe formula (2), then R¹ should not be a hydrogen atom or a lower alkylgroup and; (iii) when n is 1, Z is a group of --CH═CH-- and R¹ is ahydrogen atom, then R² should not be a hydroxyl group, a loweralkanoyloxy group, tetrahydropyranyloxy group or a pyridyloxy group. 5.The cyclic amide derivative or salt thereof according to claim 4,wherein R² is a hydroxyl group or a lower alkenyloxy group.
 6. Thecyclic amide derivative or salt thereof according to claim 4, wherein R²is a phenyl-lower alkenyloxy group, a cycloalkenyloxy group, atetrahydropyranyloxy group, or a pyridyloxy group.
 7. The cyclic amidederivative or salt thereof according to claim 5, wherein R¹ is an alkylgroup, a cycloalkyl-lower alkyl group, a carboxy-substituted lower alkylgroup, a carbamoyl-substituted lower alkyl group, an alkenyl group, alower alkanoyloxy-lower alkyl group, a hydroxyl group-substituted alkylgroup, a phenyl-lower alkyl group which may have, in the phenyl ring, 1to 3 substituents selected from the group consisting of a loweralkenyloxy group, a lower alkoxy group, a lower alkenyl group, ahydroxyl group, a lower alkyl group, a carboxyl group, a loweralkoxycarbonyl group and a group of the formula: ##STR36## or a group ofthe formula ##STR37## (wherein A is a lower alkylene group; R⁴ and R⁵are the same or different, and are each a hydrogen atom, a carbamoylgroup, a lower alkanoyl group which may have halogen atom(s), aphenylsulfonyl group which may have, in the phenyl ring, lower alkylgroup(s) as substituent(s), a lower alkoxy-lower alkyl group, a loweralkyl group, a hydroxyl group-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, or a carboxy-substitutedlower alkyl group; further, R⁴ and R⁵ may form a 5- or 6-memberedsaturated or unsaturated heterocyclic group by combining to each other,together with the adjacent nitrogen atom being bonded thereto, furtherwith or without other nitrogen atom or oxygen atom; said heterocyclicgroup may have, substituent(s) selected from the group consisting of acarbamoyl group, a carboxyl group, a cycloalkyl group and a phenyl groupwhich may have halogen atom(s) as substituent(s) in the phenyl ring). 8.The cyclic amide derivative or salt thereof according to claim 4,wherein R¹ is a hydrogen atom, a phenyl-lower alkenyl group, a phenylgroup which may have, in the phenyl ring, substituent(s) selected fromthe group consisting of a lower alkoxy group and a halogen atom, ahalogen-substituted lower alkyl group, a cycloalkenyl group, a loweralkynyl group, a naphthyl-substituted lower alkyl group, aphthalimido-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a cyano group-substitutedlower alkyl group, a group of the formula: ##STR38## (wherein A is alower alkylene group; R⁹ and R¹⁰ are the same or different, and are eacha hydrogen atom or a lower alkyl group),or a loweralkoxycarbonyl-substituted lower alkyl group.
 9. The cyclic amidederivative or salt thereof according to claim 6, wherein R¹ is an alkylgroup, a cycloalkyl-lower alkyl group, a carboxy-substituted lower alkylgroup, a carbamoyl-substituted lower alkyl group, an alkenyl group, alower alkanoyloxy-lower alkyl group, a hydroxyl group-substituted alkylgroup, a phenyl-lower alkyl group which may have, in the phenyl ring, 1to 3 substituents selected from the group consisting of a loweralkenyloxy group, a lower alkoxy group, a lower alkenyl group, ahydroxyl group, a lower alkyl group, a carboxyl group, a loweralkoxycarbonyl group and a group of the formula: ##STR39## or a group ofthe formula ##STR40## (wherein A is a lower alkylene group; R⁴ and R⁵are the same or different, and are each a hydrogen atom, a carbamoylgroup, a lower alkanoyl group which may have halogen atom(s), aphenylsulfonyl group which may have, in the phenyl ring, lower alkylgroup(s) as substituent(s), a lower alkoxy-lower alkyl group, a loweralkyl group, a hydroxyl group-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, or a carboxy-substitutedlower alkyl group; further, R⁴ and RI may form a 5- or 6-memberedsaturated or unsaturated heterocyclic group by combining to each other,together with the adjacent nitrogen atom being bonded thereto, furtherwith or without other nitrogen atom or oxygen atom; said heterocyclicgroup may have, substituent(s) selected from the group consisting of acarbamoyl group, a carboxyl group, a cycloalkyl group and a phenyl groupwhich may have halogen atom(s) as substituent(s) in the phenyl ring).10. The cyclic amide derivative or salt thereof according to claim 6,wherein R¹ is a hydrogen atom, a phenyl-lower alkenyl group, a phenylgroup which may have, in the phenyl ring, substituent(s) selected fromthe group consisting of a lower alkoxy group and a halogen atom, ahalogen-substituted lower alkyl group, a cycloalkenyl group, a loweralkynyl group, a naphthyl-substituted lower alkyl group, aphthalimido-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a cyano group-substitutedlower alkyl group, a group of the formula: ##STR41## (wherein A is alower alkylene group; R⁹ and R¹⁰ are the same or different, and are eacha hydrogen atom or a lower alkyl group), or a loweralkoxycarbonyl-substituted lower alkyl group.
 11. The cyclic amidederivative or salt thereof according to claim 7, wherein R¹ is a groupof the formula: ##STR42## (wherein A is a lower alkylene group; R⁴ andR⁵ are the same or different, and are each a hydrogen atom, a carbamoylgroup, a lower alkanoyl group which may have halogen atom(s), aphenylsulfonyl group which may have, in the phenyl ring, lower alkylgroup(s) as substituent(s), a lower alkoxy-lower alkyl group, a loweralkyl group, a hydroxyl group-substituted lower alkyl group, a loweralkoxycarbonyl-substituted lower alkyl group, or a carboxy-substitutedlower alkyl group).
 12. The cyclic amide derivative or salt thereofaccording to claim 7, wherein R¹ is a group of the formula: ##STR43##(wherein A is a lower alkylene group; R⁴ and R⁵ may form a 5- or6-membered saturated or unsaturated heterocyclic group by combining toeach other, together with the adjacent nitrogen atom being bondedthereto, further with or without other nitrogen atom or oxygen atom;said heterocyclic group may have, substituent(s) selected from the groupconsisting of a carbamoyl group, a carboxyl group, a cycloalkyl groupand a phenyl group which may have halogen atom(s) as substituent(s) inthe phenyl ring).
 13. The cyclic amide derivative or salt thereofaccording to claim 11, wherein n is
 1. 14. The cyclic amide derivativeor salt thereof according to claim 11, wherein n is 2 or
 3. 15. Thecyclic amide derivative or salt thereof according to claim 8, wherein nis
 1. 16. The cyclic amide derivative or salt thereof according to claim8, wherein n is 2 or
 3. 17. The cyclic amide derivative or salt thereofaccording to claim 4, which is selected from the group consistingof:1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-methylpropyl)-2(1H)-quinolinone;1-(cyclohexylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)acetic acidsodium salt;1-(carbamoylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneand 5,7-diallyl-3,4-dihydro-6-hydroxy-1-prenyl-2(1H)-quinolinone. 18.The cyclic amide derivative or salt thereof according to claim 4, whichis selected from the group consistingof:2-(5,7-diallyl-6-hydroxy-1,2,3,4-tetrahydro-2-oxoquinolin-1-yl)propionicacid sodium salt;1-isopropyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;1-octyl-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;1-(2-acetyloxyethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(2-hydroxyethyl)-2(1H)-quinolinone;5,7-diallyl-3,4-dihydro-6-hydroxy-1-(4-methoxybenzyl)-2(1H)-quinolinone;1-(3-allyloxybenzyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinoneand1-(cyclohexylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.19. A method for preventing or treating cataract or erythema byadministering the pharmaceutical composition according to claim
 2. 20. Amethod for preventing or treating cataract or erythema by administeringthe pharmaceutical.
 21. A method for preventing or treating cataract orerythema by administering a pharmaceutical composition containing apharmaceutically acceptable carrier and, as the effective ingredient, acyclic amide derivative or a salt thereof represented by the formula(1): ##STR44## wherein R² is a hydroxyl group, a lower alkenyloxy group,a phenyl-lower alkenyloxy group, a cycloalkenyloxy group, atetrahydropyranyloxy group, or a pyridyloxy group;R³ is a lower alkenylgroup; Z is a group of --CH₂ -- or a group of --CH═CH--; n is an integerof 1 to 3; m is 0 or 1; provided that when Z is a group of --CH₂ -- thenm is 1 and when Z is a group of--CH═CH--, then m is 0; R¹ is a hydrogenatom, an alkyl group, an alkenyl group, a phenyl-lower alkenyl group, acycloalkyl-lower alkyl group, a phenyl group which may have, in thephenyl ring, one or more substituents selected from the group consistingof a lower alkoxy group and a halogen atom, a hydroxyl group-substitutedalkyl group, a halogen-substituted lower alkyl group, a cycloalkenylgroup; a lower alkynyl group, a phenyl-lower alkyl group which may have,in the phenyl ring, 1 to 3 substituents selected from the groupconsisting of a lower alkenyloxy group, a lower alkoxy group, a loweralkenyl group, a hydroxyl group, a lower alkyl group, a carboxyl group,a lower alkoxycarbonyl group and a group of the formula: ##STR45## anaphthyl-substituted lower alkyl group, a phthalimido-substituted loweralkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, agroup of the formula: ##STR46## (wherein A is a lower alkylene group; R⁴and R⁵ are the same or different, and are each a hydrogen atom, acarbamoyl group, a lower alkanoyl group which may have one or morehalogen atoms, a phenylsulfonyl group which may have, in the phenylring, one or more lower alkyl groups as substituents, a loweralkoxy-lower alkyl group, a lower alkyl group, a hydroxylgroup-substituted lower alkyl group, a lower alkoxycarbonylgroup-substituted lower alkyl group, or a carboxy-substituted loweralkyl group; further R⁴ and R¹ may form a 5- or 6-membered saturated orunsaturated hereocyclic group by combining to each other, together withthe adjacent nitrogen atom being bonded thereto, further with or withoutother nitrogen atom or oxygen atom; said heterocyclic group may have oneor more-substituents selected from the group consisting of a carbamoylgroup, a carboxyl group, a cycloalkyl group and a phenyl group which mayhave one or more halogen atoms as substituents in the phenyl ring);alower alkanoyloxy-lower alkyl group, a cyano group-substituted loweralkyl group, a group of the formula: ##STR47## (wherein A is a loweralkylene group; R⁹ and R¹⁰ are the same or different, and are each ahydrogen atom or a lower alkyl group), a carboxy-substituted lower alkylgroup, a lower alkoxycarbonyl-substituted lower alkyl group or acarbamoyl-substituted lower alkyl group.
 22. The pharmaceuticalcomposition of claim 1, wherein R² is a hydroxyl group, a loweralkenyloxy group, a phenyl-lower alkenyloxy group, a cycloalkenyloxygroup or a tetrahydropyranyloxy group; Z is a group of --CH₂ --; and mis
 1. 23. The cyclic amide derivative or a salt thereof of claim 4,wherein R² is a hydroxyl group, a lower alkenyloxy group, a phenyl-loweralkenyloxy group, a cycloalkenyloxy group or a tetrahydropyranyloxygroup; Z is a group of --CH₂ --; and m is 1.